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.
This pioneering innovation is consistent with the trend to bring medical services to places more convenient for consumers and was spurred by a study which showed men twice as likely to have heart attacks than women
Patient-facing healthcare gets a boost with this novel program to offer a diagnostic service in locations frequented by men. In an attempt to decrease heart attacks in the UK, the country’s National Health Service (NHS) now employs a novel approach to prevention—bringing blood pressure screenings to the public in barbershops.
This is yet another example of moving diagnostics services out of traditional healthcare settings and reaching people in places that they visit in their daily lives. True, this is a blood pressure test. But once the service is established, it should be easy to collect other types of clinical laboratory specimens at barbershops as well. And if this approach enables healthcare policy makers to reach a population that needs further diagnostic tests—and it’s economically feasible—that may encourage adoption of this approach for other types of health screenings.
According to The Guardian, the screenings will be available at “barbershops, churches, mosques, community centers, and dominoes clubs.” The intention is to ensure screenings are more accessible, to educate the public, and to encourage lifestyle changes that lead to prevention.
This consumer-directed approach to healthcare by the NHS appears to be making a difference. The new screening locations already show promise. In 2023, efforts brought in 150,000 community-based blood pressure screenings by August. That more than doubled the previous year’s 58,000 that were performed by May, The Guardian noted.
“With the number of people living with major illnesses including heart disease and other cardiovascular conditions set to grow substantially over the coming years, it has never been more important to put in place preventive measures like easy-to-access blood pressure checks that can pick up the early signs and risks,” said David Webb (above), Chief Pharmaceutical Officer for England, NHS England, in a news release. Should this program succeed, it’s likely other types of clinical laboratory test specimens could also be collected in barbershops and other convenient locations. (Photo copyright: Paul Stuart/The Pharmaceutical Journal.)
Importance of Screening
According to the UK’s Health Foundation, more than 9.1 million people will have a major illness by 2040, and figures show an increase of 2.5 million from 2019 reports. These figures are “why prevention and early intervention tools such as community blood pressure checks are key priorities for the NHS,” the NHS news release states.
“Having high blood pressure raises the risk of a heart attack, but many men and women remain unaware they may be affected because typically there are no symptoms,” The Guardian reported. “Every year there are 100,000 NHS hospital admissions due to heart attacks—one every five minutes.”
The NHS’ moves were spurred by recent findings announced at the European Society of Cardiology’s 2023 annual meeting. The world’s largest heart conference showcased a 22-year-long study examining the gender-specific risks of cardiovascular diseases. The results clearly showed that men were twice as likely to experience heart attacks and peripheral artery disease than women.
The University of Aberdeen conducted the study which ran from 1993-2018 and followed 20,000 individuals over the age of 40. While researchers noted many factors—such as ethnicity, body mass index (BMI), physical activity, deprivation, consumption of alcohol, and cigarette smoke—a clear defining line landed between male and female participants, The Guardian reported. Additionally,“Men are also more likely to experience a heart attack at a younger age than women.”
And, according to the study, while cardiovascular disease was higher for men during their entire lifetime, “sex differences were most pronounced for myocardial infarction and peripheral artery disease, followed by atrial fibrillation, heart failure, and cardiovascular mortality,” The Guardian reported, adding, “Men also have a 50% higher risk of heart failure and atrial fibrillation. The study discovered that men have a 42% higher risk of dying from cardiovascular disease. The research did not look at why.”
Education Part of Prevention
“Men should start looking early at-risk factors, like obesity, lack of exercise, smoking, alcohol consumption, and reach out to their GP to get those things addressed. The earlier the better. There’s no harm in minimizing your cardiovascular risk,” Tiberiu Pana, MRes, lead researcher and honorary research fellow at the University of Aberdeen, told The Guardian. Pana is also a junior doctor in the NHS and focuses on cardiovascular epidemiology and the brain-heart interactions.
“Coronary heart disease is the most common killer of men. There’s never been a better time to get physically active and replace that pub session with an extra session in the gym,” cardiologist Sonya Babu-Narayan, MBBS, Associate Medical Director at the British Heart Foundation, told The Guardian. Babu-Narayan is also a consultant cardiologist at Royal Brompton Hospital.
Women, however, are not exempt from the risk of heart disease.
“If we consider the effects of heart disease over a lifetime, we need to remember that it costs lives for both men and women,” Babu-Narayan said. “With 30,000 women in the UK admitted to hospital with a heart attack each year, it is vital to dismantle the dogma that heart attacks are the preserve of men. Regardless of gender, cardiovascular disease is the world’s biggest killer and there are steps everyone can take to reduce their risks.”
In addition to the aforementioned community locations for screenings, NHS has launched a few other approaches to meet patients on their own turf.
A mobile blood pressure service named How’s Thi Ticker in Barnsley, South Yorkshire, “travels around local neighborhoods including to barber shops, supermarkets, and community centers, seeing more than a third of people referred to pharmacists with high blood pressure—freeing up GPs and catching early signs of heart attack and stroke risk,” according to the NHS news release.
Future Showing Further Promise
As the process continues, NHS expects to prevent 1,350 cardiovascular events every year, and expects to see 2.5 million more blood pressure checks performed in the community in England as a result of the endeavor, The Guardian noted.
One can only imagine how far this trend can go. Clinical laboratory managers and pathologists can expect healthcare policy makers in the UK to continue their efforts to bring needed diagnostic testing to underserved populations in accessible ways. This should be a win-win financially and in improving the health of the country’s population.
The focus of the ongoing GenoVA study is to “determine the clinical effectiveness of polygenic risk score testing among patients at high genetic risk for at least one of six diseases measured by time-to-diagnosis of prevalent or incident disease over 24 months,” according to the National Institutes of Health.
The scientists used data obtained from 36,423 patients enrolled in the Mass General Brigham Biobank. The six diseases they researched were:
The polygenic scores were then tested among 227 healthy adult patients to determine their risk for the six diseases. The researchers found that:
11% of the patients had a high-risk score for atrial fibrillation,
7% for coronary artery disease,
8% for diabetes, and
6% for colorectal cancer.
Among the subjects used for the study:
15% of the men in the study had a high-risk score for prostate cancer, and
13% of the women in the study had a high score for breast cancer.
The researchers concluded that the implementation of PRS may help improve disease prevention and management and give doctor’s a way to assess a patient’s risk for these conditions. They published their findings in the journal Nature Medicine, titled, “Development of a Clinical Polygenic Risk Score Assay and Reporting Workflow.”
“We have shown that [medical] laboratory assay development and PRS reporting to patients and physicians are feasible … As the performance of PRS continues to improve—particularly for individuals of underrepresented ancestry groups—the implementation processes we describe can serve as generalizable models for laboratories and health systems looking to realize the potential of PRS for improved patient health,” the researchers wrote.
Using PRS in Clinical Decision Support
Polygenetic risk scores examine multiple genetic markers for risk of certain diseases. A calculation based on hundreds or thousands of these genetic markers could help doctors and patients make personalized treatment decisions, a core tenet of precision medicine.
“As a primary care physician myself, I knew that busy physicians were not going to have time to take an entire course on polygenic risk scores. Instead, we wanted to design a lab report and informational resources that succinctly told the doctor and patient what they need to know to make a decision about using a polygenic risk score result in their healthcare,” epidemiologist Jason Vassy, MD, told The Harvard Gazette. Vassy is Associate Professor, Harvard Medical School at VA Boston Healthcare System and one of the authors of the research.
“This is another great example of precision medicine,” Jason Vassy, MD (above), Adjunct Assistant Professor, General Internal Medicine at Boston University School of Medicine, told WebMD. “There’s always been a tantalizing idea that someone’s genetic makeup might help tailor preventative medicine and treatment.” Personalized clinical laboratory testing is increasingly becoming based on an individual’s genetics. (Photo copyright: Harvard Medical School.)
Increasing Diversity of Patients in Genomic Research
The team did encounter some challenges during their analysis. Because most existing genomic research was performed on persons of European descent, the risk scores are less accurate among non-European populations. The researchers for this study addressed this limitation by applying additional statistical methods to qualify accurate PRS calculations across multiple racial groups.
“Researchers must continue working to increase the diversity of patients participating in genomics research,” said Matthew Lebo, PhD, Chief Laboratory Director, Laboratory Molecular Medicine, at Mass General Brigham and one of the authors of the study. “In the meantime, we were heartened to see that we could generate and implement valid genetic scores for patients of diverse backgrounds,” he told The Harvard Gazette.
The team hopes the scores may be utilized in the future to help doctors and patients make better decisions regarding preventative care and screenings.
“It’s easy to say that everyone needs a colonoscopy at age 45,” Vassy told WebMD. “But what if you’re such a low risk that you could put it off for longer? We may get to the point where we understand risk so much that someone may not need one at all.”
Future of PRS in Clinical Decision Making
The scientists plan to enroll more than 1,000 patients in a new program and track them for two years to assess how medical professionals use PRS in clinical care. It is feasible that patients who are at high risk for certain diseases may opt for more frequent screenings or take preventative medicines to mitigate their risk.
“Getting to that point will take time,” Vassy added. “But I can see this type of information playing a role in shared decision making between doctor and patient in the near future.”
The team also established resources and educational materials to assist both doctors and patients in using the scores.
“It’s still very early days for precision prevention,” Vassy noted, “but we have shown it is feasible to overcome some of the first barriers to bringing polygenic risk scores into the clinic.”
More research and studies are needed to prove the effectiveness of using PRS tests in clinical care and determine its role in customized treatment plans based on personal genetics. Nevertheless, pathologists and medical scientists will want to follow the GenoVA study.
“It is probably most helpful to think of polygenic risk scores as a risk factor for disease, not a diagnostic test or an indication that an individual will certainly develop the disease,” Vassy said. “Most diseases have complex, multifactorial etiologies, and a high polygenic risk score is just one piece of the puzzle.”
Pathologists and clinical laboratory managers may want to stay informed as researchers in the GenoVA study tease new useful diagnostic insights from their ongoing study of the whole human genome. Meanwhile, the GenoVA team is moving forward with the 1,000-patient study with the expectation that this new knowledge may enable earlier and more accurate diagnoses of the health conditions that were the focus of the GenoVA study.
Many companies want to adapt consumer wearables to monitor health conditions, including biomarkers tested by medical laboratories
Clinical laboratory managers know that wearable devices for monitoring biophysical functions or measuring biomarkers are becoming more complex and capable thanks to advances in miniaturization, informatics, software, and artificial intelligence machine learning that enable new functions to be developed and proved to be accurate.
In September, Fitbit (NYSE:FIT), took that a step further. The San Francisco-based maker of personal fitness technology, “received 510(k) clearance from the US Food and Drug Administration (FDA), as well as Conformité Européenne (CE marking) in the European Union, for its electrocardiogram (ECG) app to assess heart rhythm for atrial fibrillation (AFib),” according to a press release.
The fact that Google is currently in the process of acquiring Fitbit for $2.1 billion may indicate that wearable devices to help physicians and patients diagnose and monitor health conditions will be big business in the future.
The new ECG app is available on Fitbit Sense (above), an “advanced health smartwatch.” To use the app, wearers place their finger and thumb to the stainless-steel corners on the watch and remain still for 30 seconds. The app analyzes the heart’s rhythm for signs of AFib. Individuals can take readings of their heart rhythm at any time, monitor for irregularities, and save and share the data. (Photo copyright: Fitbit.)
Helping Doctors ‘Stay Better Connected’ to Their Patients
“Helping people understand and manage their heart health has always been a priority for Fitbit, and our new ECG app is designed for those users who want to assess themselves in the moment and review the reading later with their doctor,” said Eric Friedman, Fitbit co-founder and Chief Technology Officer, in the press release.
Prior to submitting the device for approval to regulatory agencies, Fitbit conducted the clinical trial in regions throughout the US to evaluate the device’s ability to accurately detect AFib from normal sinus rhythm and generate ECG traces. The researchers proved that their algorithm was able to detect 98.7% of AFib cases (sensitivity) and was able to accurately identify normal sinus rhythms (specificity) in 100% of the cases.
Venkatesh Raman, MD, interventional cardiologist and Medical Director of the Cardiac Catheterization Lab at 609-bed MedStar Georgetown University Hospital, was Principal Investigator for the clinical study on Fitbit’s ECG app. “Physicians are often flying blind as to the day-to-day lives of our patients in between office visits. I’ve long believed in the potential for wearable devices to help us stay better connected, and use real-world, individual data to deliver more informed, personalized care,” he said in the press release.
“Given the toll that AFib continues to take on individuals and families around the world,” Raman continued, “I’m very enthusiastic about the potential of this tool to help people detect possible AFib—a clinically important rhythm abnormality—even after they leave the physician’s office.”
Fitbit ECG App Receives European CE Marking
In addition to receiving approval for the Fitbit ECG app in the US, the device also received CE marking (Conformité Européenne) for use in some European countries.
In October 2020, the app was made available to Fitbit Sense users in the US, Austria, Belgium, Czech Republic, France, Germany, Ireland, Italy, Luxembourg, the Netherlands, Poland, Portugal, Romania, Spain, Sweden, Switzerland, and the United Kingdom. The device also received approval for use in Hong Kong and India.
It is estimated that more than 33.5 million people globally have AFib, an irregular heart rhythm (arrhythmia) that can lead to stroke, blood clots, or heart failure. The American Heart Association estimates that at least 2.7 million Americans currently live with the condition. The most common symptoms experienced by those with the condition are:
Irregular heartbeat,
Heart palpitations (rapid, fluttering, quivering or pounding),
Lightheadedness,
Extreme fatigue,
Shortness of breath, and
Chest pain.
Risk factors for AFib include advancing age, high blood pressure, obesity, diabetes, European ancestry, hyperthyroidism, chronic kidney disease, alcohol use, smoking, and known heart issues such as heart failure, ischemic heart disease, and enlargement of the chambers on the left side of the heart.
According to the Centers for Disease Control and Prevention (CDC), there are more than 454,000 hospitalizations annually in the US that list AFib as the primary diagnosis. In 2018, AFib was mentioned on 175,326 death certificates with the condition being the underlying cause of death in 25,845 of those cases.
The CDC reports that cases are increasing and projects that by 2030 12.1 million people in the US will have AFib. Many people are asymptomatic of the illness and do not know they have it, which can make AFib more difficult to diagnose.
“Early detection of AFib is critical, and I’m incredibly excited that we are making these innovations accessible to people around the world to help them improve their heart health, prevent more serious conditions, and potentially save lives,” Friedman said, in a statement.
Clinical laboratory managers should monitor these developments closely. Fitbit’s FDA clearance and CE Marking of its ECG app suggest this trend is accelerating.
More than 312 teams applied for the completion and the prize-winning hand-held device uses clinical laboratory assays to diagnose up to 34 different medical conditions
Star Trek fans among clinical laboratory manager and pathologist will be excited to learn that the winners of the Qualcomm Tricorder XPRIZE were announced earlier this year, five years after the contest began. The purpose of the XPRIZE competition was to challenge teams to create a mobile integrated diagnostic device that weighed less than five pounds and had the ability to monitor health metrics and diagnose 13 specific health conditions. The premise for the contest was inspired by the Star Trek medical tricorder that was first conceptualized on the television show “Star Trek” in the 1960s.
In the popular science-fiction show, the tricorder was a multifunctional hand-held device used for sensor scanning, data analysis, and recording data. The name “tricorder” was an abbreviation for the full name of the gadget, “tri-function recorder,” which referred to the three primary functions of the device.
Based in Culver City, Calif, the XPRIZE Foundation is a non-profit organization that creates and oversees prestigious technological competitions for the purpose of prompting innovations that could benefit humanity.
Handheld Device That Can Perform Multiple Clinical Laboratory Assays
The Qualcomm Tricorder XPRIZE competition was launched in January 2012. Participants had until August 2013 to register for the contest. The qualifying round was held the following August. Three hundred and twelve teams entered the competition. Qualifiers had until March 2015 to design and build their prototypes. Consumer testing on the products began in September 2016 and the winners were announced in April 2017.
The top prize of $2.6 million was awarded to Final Frontier Medical Devices, the team led by Basil Harris, MD, an emergency room physician with a PhD in Materials Engineering led the team, along with his network engineer brother, George Harris.
Basil Leaf Technologies, founded by Basil Harris, MD, PhD, FACEP (above center); and his brother George, a Network Engineer (second from left), is a medical technology company headquartered in Paoli, Pa. Their winning entry, called DxtER (pronounced Dexter), is a small FDA-approved group of medical devices that enable consumers to diagnose illnesses at home or remotely and share that data with healthcare providers. (Photo copyright: XPRIZE Foundation.)
The collection of FDA-approved devices that make up the “tricorder” includes sensors designed to gather data about vital signs, body chemistry, and biological functions. The DxtER device walks patients through the self-diagnosis of 34 medical conditions. The instruments include:
· A compact spirometer that calculates lung strength;
DxtER communicates with a tablet and/or smartphone-based app. Since the components are FDA-approved, diagnostic test results can be taken directly to healthcare professionals.
“You can [receive the] results and take them to the ER or to your physician or whoever’s helping you, and they can build off those results,” George Harris explained in an Engadget article. “They don’t have to start back at square one. They can jump off at that point and move on with their healthcare.”
Basil Leaf Technologies’ DxtER “tricorder” (above) enables the user to self-diagnose up to 34 medical conditions. Each individual component is FDA-approved, so hospital physicians can rely on the accuracy of the test results. (Photo copyright: XPRIZE Foundation.)
According to the contest website, “at the heart of DxtER is an artificially intelligent engine that learned to diagnose by integrating years of experience in clinical emergency medicine with data analysis from actual patients having a variety of medical conditions and outcomes.”
“It is very exciting that our vision of mobile, personalized patient-centric healthcare is getting closer to becoming a reality thanks to the great work of the Qualcomm Tricorder XPRIZE teams,” declared Paul E. Jacobs, PhD, Executive Chairman of Qualcomm Incorporated (NASDAQ:QCOM) in an XPRIZE press release. “Creating technology breakthroughs in an industry as complex as healthcare is quite a milestone, and what these teams accomplished is a great stepping stone to making mobile healthcare a viable option across the world.”
DxtER Functions Like a Mobile Medical Laboratory
In addition to the $2.6-million prize, Qualcomm Foundation is giving the Basil Leaf team $3.8 million to further develop the device. This amount includes a:
· $2.5 million proposal grant to the University of California San Diego; and a
· $1.6-million gift from the Roddenberry Foundation to adapt the tricorder for hospital use in the developing world.
The XPRIZE competition required contestants to create a tricorder device that could accurately diagnose 13 health conditions. This included 10 core conditions and a choice of three elective health conditions. The devices also needed to be able to acquire five real-time vital signs:
1. Blood pressure;
2. Heart rate;
3. Oxygen saturation;
4. Respiratory rate; and
5. Temperature.
The 10 core conditions the devices had to be able to identify were:
It is notable that the TriCorder XPRIZE—with its $2.6 million prize—generated entries from 312 teams. Pathologists and clinical laboratory managers can take this high number of entrants as a sign that the ongoing advances in technology are poised to support a new generation of very small medical lab testing devices. Thus, miniaturized diagnostic technologies, when combined with more sophisticated computing chips and software are making it simpler and more feasible to pack multiple diagnostic instruments into a hand-held package.