Multiple studies have shown that people with darker skin pigmentation run a higher risk of being misdiagnosed and undertreated than patients with lighter skin due to inaccurate oxygen level readings
Now, scientists at multiple institutions are working to improve the basic pulse oximeter’s design by making it capable of measuring multiple biomarkers, as well as addressing long-standing inaccuracies in the device when used on people with darker skin pigmentation.
This ongoing research demonstrates how new technologies are enabling innovators to add useful functions to standard, well-accepted devices.
Valencia Koomson, PhD (above), Associate Professor, Electrical and Computer Engineering, and head of the Advanced Integrated Circuits and Systems Lab at Tufts University, has developed a pulse oximeter that measures oxygenation in tissue, rather than in blood. Her approach could ensure patients with darker skin pigmentation will be accurately diagnosed at the point-of-care. Though generally not used in clinical laboratory settings, medical technologists will be interested to learn of these new innovations in pulse oximeters. (Photo copyright: Tufts University.)
Measuring Tissues Instead of Blood
The pulse oximeter—a device that attaches to a person’s finger—uses red and infrared light to measure blood oxygen saturation (SpO2) and display pulse rate.
Studies in 2022 that looked into how hospitals administered oxygen to different patients found that inconsistent pulse oximeter readings could cause caregivers to administer less oxygen than is actually needed to people with darker skin pigmentation.
This is because melanin in the skin can interfere with “absorption of light used to measure oxygenated blood in a person’s finger,” according to a National Science Foundation (NSF) news story. Such inaccurate pulse oximeter readings can lead to “inaccurate readings and poorer treatment outcomes” for people with dark skin tones, the NSF wrote.
“Addressing this problem will require innovation in pulse oximeter design and revised regulatory standards,” said Valencia Koomson, PhD, Associate Professor, Electrical and Computer Engineering, Tufts University, Medford, Massachusetts, in the NSF news story.
Koomson, who leads the Advance Integrated Circuit and Systems Lab at Tufts, has developed a prototype pulse oximeter device, which NSF explained, measures oxygenation in biological tissues instead of blood.
“My lab’s work on pulse oximeter devices will provide an alternative technology to address many confounding factors that affect pulse oximeter accuracy, including skin pigmentation, motion artifact, and others,” Koomson said.
National Public Radio (NPR) said Koomson’s device has built-in “technology that can measure a person’s skin tone.”
“We can send more light if there’s a higher level of melanin present, so that melanin doesn’t become a confounding factor that obscures our results,” Koomson told NPR.
Another Pulse Oximeter Redesign
Another new approach to pulse oximetry was developed at Brown University in Providence, Rhode Island.
Rutendo Jakachira, Research Assistant, School of Engineering, and a PhD student in physics, turned to new optical techniques to address the challenge of oxygen saturation levels in dark skin tones, according to a Brown University news release.
Jakachira and Kimani Toussaint, PhD, Professor of Engineering and Senior Associate Dean in the School of Engineering, say they have created possibly the first LED-based light source to emit radially polarized light.
When the LED passes light through a person’s finger, the device calculates the amount of light the hemoglobin in the blood absorbed, NPR explained.
“We did a preliminary study on about five people, and although it was a small study, the results are promising,” said Jakachira, who plans a larger study and clinical trial.
Study Suggests Patients with Darker Skin May Have Received Delayed COVID-19 Care
The researchers analyzed electronic health record (EHR) data from 43,753 patients at Sutter Health in Sacramento, California, who had SpO2 measurements done between January 2020 and February 2022, and 8,735 patients seen for COVID-19 between July 2020 and February 2021 in the hospital’s emergency department.
In their AJE paper, they wrote, “We investigated whether or not pulse oximetry systematically underestimated oxygen saturation in patients who identified as NHB [non-Hispanic Black/African-American] as compared with NHW [non-Hispanic White] counterparts. We also assessed whether or not differences in oxygen saturation measurement affected hospital admission, care delivered, or return to the hospital post discharge among patients with COVID-19.
“We found evidence of differential pulse oximeter measurement error in NHB individuals, resulting in nonrandom overestimation of blood oxygenation as compared with NHW individuals. NHB individuals were also more likely to have hypoxemia [abnormally low oxygen levels in the blood] not detected by pulse oximetry.
“For NHB patients presenting in the ED with COVID-19, we found that overestimation of oxygen saturation was associated with underestimation of the need for admission and underestimation of the need for treatment with dexamethasone and supplemental oxygen. Additionally, we observed associated delays in dexamethasone initiation and initiation of oxygen supplementation.
“There are also broader implications beyond COVID-19, as differential pulse oximeter accuracy has the potential to exacerbate disparities for any condition that relies upon blood oxygenation measurement to inform clinical decision-making.”
Importance of Accurate Readings
Developing pulse oximeters that are accurate for all people, regardless of skin tone, is clearly an important breakthrough. Medical laboratory leaders and pathologists recognize that SpO2 data—along with clinical laboratory test results—are critical for successful diagnostics and treatment. Thus, new technologies that add useful functions to well-accepted devices are positive developments and worth watching.
Understanding why some people display no symptoms during a COVID-19 infection could lead to new precision medicine genetic tests medical labs could use to identify people with the mutated gene
New research from the University of California San Francisco (UCSF) may explain why some people could get COVID-19 but never test positive on a clinical laboratory test or develop symptoms despite exposure to the SARS-CoV-2 coronavirus.
According to the UCSF study, variations in a specific gene in a system of genes responsible for regulating the human immune system appears to be the factor in why about 10% of those who become infected with the virus are asymptomatic.
These scientific insights did not receive widespread news coverage but will be of interest to clinical laboratory managers and pathologists who oversee SARS-CoV-2 testing in their labs.
“Some people just don’t have symptoms at all,” Jill Hollenbach, PhD (above), Professor of Neurology atUCSF’s Weill Institute for Neurosciences and lead researcher in the study, told NBC News. “There’s something happening at a really fundamental level in the immune response that is helping those people to just completely wipe out this infection.” Identifying a genetic reason why some people are asymptomatic could lead to new precision medicine clinical laboratory diagnostics for COVID-19. (Photo copyright: Elena Zhukova /University of California San Francisco.)
Fortunate Gene Mutation
According to the Centers for Disease Control and Prevention’s (CDC) COVID Data Tracker, as of April 5, 2023, a total of 104,242,889 COVID-19 cases have been reported in the United States. However, according to a CDC Morbidity and Mortality Weekly Report (MMWR), “Traditional methods of disease surveillance do not capture all COVID-19 cases because some are asymptomatic, not diagnosed, or not reported; therefore, [knowing the true] proportion of the population with SARS-CoV-2 antibodies (i.e., seroprevalence) can improve understanding of population-level incidence of COVID-19.”
She also participates in the COVID-19 HLA and Immunogenetics Consortium, a group of academic researchers, clinical laboratory directors, journal editors, and others who examine the role of HLA variations in determining COVID-19 risk.
Hollenbach’s research identified an HLA variant—known as HLA-B*15:01—that causes the human immune system to react quickly to SARS-CoV-2 and “basically nuke the infection before you even start to have symptoms,” she told NPR.
“It’s definitely luck,” she added. “But, you know, this [gene] mutation is quite common. We estimate that maybe one in 10 people have it. And in people who are asymptomatic, that rises to one in five.”
“HLA variants are among the strongest reported associations with viral infections,” the UCSF study notes. So, the researchers theorized that HLA variations play a role in asymptomatic SARS-CoV-2 infections as well.
To conduct their study, shortly after the SARS-CoV-2 outbreak in 2020, the researchers recruited approximately 30,000 volunteer bone marrow donors from the National Marrow Donor Program to respond to periodic questions via a smartphone app or website. Because HLA variations can determine appropriate matches between donors and recipients, the database includes information about their HLA types.
Each week, respondents were asked to report if they had been tested for SARS-CoV-2. Each day, they were asked to report whether they had symptoms associated with COVID-19. “We were pretty stringent in our definition of asymptomatic,” Hollenbach told NBC News. “[The respondents couldn’t] even have a scratchy throat.”
The researchers eventually identified a cohort of 1,428 people who had tested positive for SARS-CoV-2 between February 2020 and April 30, 2021, before vaccines were widely available. Among these individuals, 136 reported no symptoms for two weeks before or two weeks after a positive test.
“Overall, one in five individuals (20%) who remained asymptomatic after infection carried HLA-B*15:01, compared to 9% among patients reporting symptoms,” the researchers wrote in their medRxiv preprint. Study participants with two copies of the gene were more than eight times more likely to be asymptomatic.
The UCSF researchers also looked at four other HLA variants and found none to be “significantly associated” with lack of symptoms. They confirmed their findings by reproducing the HLA-B association in two additional independent cohorts, one from an earlier study in the UK and the other consisting of San Francisco-area residents.
Individuals in the latter group had either tested positive for SARS-CoV-2 or reported COVID symptoms, and their DNA was analyzed to determine their HLA types.
Pre-existing T-Cell Immunity May Reduce Severity of COVID-19 Infection
The UCSF researchers also attempted to determine how HLA-B*15:01 plays a role in knocking out SARS-CoV-2 infections. They noted previous research that indicated previous exposure to seasonal coronaviruses, such as common cold viruses, could limit the severity of COVID-19. The scientists hypothesized that pre-existing T-cell immunity in HLA-B carriers may be the key.
The COVID-19 HLA and Immunogenetics Consortium website describes how HLA and T-cells work together to ward off disease. HLA “proteins are found on the surface of all cells except red-blood cells.” They’re “like windows into the inner workings of a cell,” and T-cells use the molecules to determine the presence of foreign proteins that are likely signs of infection. “Activated T-cells can kill infected cells, or activate B-cells, which produce antibodies in response to an infection,” the website explains.
Hollenbach’s research team analyzed T-cells from pre-pandemic individuals and observed that in more than half of HLA-B carriers, the T-cells were reactive to a SARS-CoV-2 peptide. The scientists corroborated the hypothesis by examining crystal structures of the HLA-B*15:01 molecule in the presence of coronavirus spike peptides from SARS-CoV-2 and two other human coronaviruses: OC43-CoV and HKU1-CoV.
“Altogether, our results strongly support the hypothesis that HLA-B*15:01 mediates asymptomatic COVID-19 disease via pre-existing T-cell immunity due to previous exposure to HKU1-CoV and OC43-CoV,” the researchers wrote.
Can Genes Prevent COVID-19 Infections?
Meanwhile, researchers at The Rockefeller University in New York City are attempting to go further and see if there are mutations that prevent people from getting infected in the first place. NPR reported that they were seeking participants for a study seeking to identify so-called “superdodger” genes.
Study participants identified as possibly having superdodger genes receive a kit designed to collect saliva samples, after which the researchers sequence the respondents’ genomes. “We hope that in a group of 2,000 to 4,000 people, some people will have genetic mutations that tell us why they’re resistant to infection,” Casanova told NPR.
All this genetic research is in very early stages. But results are promising and may lead to new precision medicine clinical laboratory tests for identifying people who are predisposed to having an asymptomatic response to COVID-19 infection. That in turn could help scientists learn how to moderate or even eliminate symptoms in those unfortunate people who suffer the typical symptoms of the disease.
Project aims to create a new pangenome for genetic testing that will ensure better clinical laboratory testing and healthcare outcomes
Recent advances in genetics are motivating some scientists to proclaim the need to update the existing “master human genome”—currently based on a single individual’s genetic sequence—to make it more inclusive. This international research effort will have implications for personalized clinical laboratory testing and precision medicine.
Genetic scientists at the Human Pangenome Reference Consortium (HPRC), a project funded by the National Human Genome Research Institute (NHGRI), are working “to sequence and assemble genomes from individuals from diverse populations in order to better represent [the] genomic landscape of diverse human populations,” according to the organization’s website.
The project plans to evaluate a wide variety of reference genomes and develop a more diverse human pangenome (a multi-genome reference sequence) that will contain a larger cross-section of the human population. The HPRC scientists will be looking at genomes from specific countries, including Denmark, Japan, South Korea, Sweden, and the United Arab Emirates, The Guardian reported.
The increased diversity of reference genetic data will enable genomic researchers to increase the accuracy of precision medicine diagnostics and clinical laboratory testing.
“One person is not representative of the world,” Pui-Yan Kwok, MD, PhD (above), Henry Bachrach Distinguished Professor, Cardiovascular Research Institute at the University of California, San Francisco, told The Guardian. “As a result, most genome sequencing is fundamentally biased.” And that bias, the researchers claim, affects the accuracy of clinical laboratory treatments and diagnostics. (Photo copyright: UCSF.)
Reference Genome for Genetic Sequencing is Based on One Person
Launched in 1990, The Human Genome Project studied all DNA in a select set of organisms. The project completed its first sequence of the human genome in 2003, which became the reference genome for thousands of genomic discoveries since then.
But there’s a problem.
Although a revolutionary breakthrough in genetic sequencing, that reference genome came from just one person. This means a significant portion of the human population is not represented in genetic research, and that bias, according to some scientists, “limits the kind of genetic variation that can be detected, leaving some patients without diagnoses and potentially without proper treatment,” according to The Guardian.
“Getting the right medicine to the right patient at the right time is the tagline,” Neil Hanchard, MD, DPhil, physician scientist and senior investigator for precision health research at the NHGRI in Bethesda, Maryland, told The Guardian.
The HPRC’s goal is to help mitigate reference biases that could hamper disease diagnoses and ensure all populations receive the best treatments for illness.
According to its website, the organization’s main purpose includes:
Gene sequencing from a diverse set of samples with the newest technologies.
Fostering an ecosystem of assembly and pangenome tools.
Creating and releasing high-quality assemblies and pangenomes.
Embedding a team of scholars to address ethical, legal, and social implications of their work.
Forming international partnerships for the research.
HPRC Scientists Find Never-Sequenced Genetic Variants in Africa
Standard gene sequencing works by dividing DNA into tiny portions known as short reads, then sequencing and organizing the reads into a genome using an existing reference as a guide. However, this process renders larger blocks of variants, called structural variants (SVs), more difficult to read or even remain undetected, which can translate to a sequence that does not completely represent personal variations.
In 2019, the HPRC team of scientists analyzed genetic samples from 154 people from various parts of the world and discovered SV content that was missing from their reference sequence. A further study of genetic samples from 338 individuals that examined only extra inserted DNA detected the presence of almost 130,000 new sequences.
More recently, the HPRC researchers sampled 426 individuals from 50 ethnolinguistic groups from Africa and discovered a few million new single nucleotide variants (SNVs). Most of these distinct SNVs derived from populations that had not been previously sampled.
“We haven’t even touched SVs,” Hanchard told The Guardian. “But our preliminary data suggests it’s going to be more of the same.”
“We may miss risk variants in those regions not represented in the reference,” he added.
HPRC Receives Clearance from NHGRI to Continue Research
Hanchard recognizes the benefits of regional references in genomic sequencing and is optimistic about the future of genomics and the ability to sequence more diverse populations.
“I would love to get to a point where everyone feels represented and that this is for them, as much as it is for any particular group,” he told The Guardian. “We are from one humanity, that’s the important part.”
On February 13, the HPRC received concept clearance for renewal of the program from the NHGRI, which plans to commit up to $10 million in total costs per year for the program over the next five years.
Genetic sequencing continues to emerge as a vital tool in the diagnoses and treatment of diseases. Ensuring that as many diverse populations as possible are included in genomic research is an important element for precision medicine and optimal healthcare.
Clinical laboratory managers and pathologists will want to stay updated on these developments, because much of this new knowledge about the pangenome will need to be incorporated when interpreting genetic sequences and developing diagnoses in support of personalized medicine.
Viral reservoir could be behind persistence, says study, which also suggests a blood biomarker could be found for clinical laboratory testing
Microbiologists and virologists working closely with physicians treating long COVID-19 patients will gain new insights in a study that found coronavirus spike protein in COVID-19 patients’ blood up to 12 months after diagnosis. The researchers believe their findings could be used to develop a clinical laboratory biomarker for long COVID-19.
Researchers at Brigham and Women’s Hospital and Massachusetts General Hospital said medical experts are not sure why some people have unwelcome symptoms weeks and months after a positive COVID-19 diagnosis, while others clear the infection without lingering effects.
The scientists believe if this work is validated, clinical laboratories might gain an assay to use in the diagnosis of long COVID-19.
“The half-life of spike protein in the body is pretty short, so its presence indicates that there must be some kind of active viral reservoir,” said David Walt, PhD (above), Professor of Pathology, Brigham and Women’s Hospital, and lead author of the study that found coronavirus spike protein in long COVID patients. The study findings indicate a potential clinical laboratory biomarker for long COVID-19. (Photo copyright: Brigham and Women’s Hospital.)
Viral Reservoir Possibly Behind Long COVID-19
The study suggests that SARS-CoV-2 finds a home in the body, particularly the gastrointestinal tract, “through viral reservoirs, where it continues to release spike protein and trigger inflammation,” Medical News Today reported.
Lead author of the study David Walt, PhD, Professor of Pathology, Brigham and Women’s Hospital and the Hansjörg Wyss Professor Biologically Inspired Engineering at Harvard Medical School, told The Guardian he “was motivated to carry out the study after earlier research by his colleagues detected genetic material from the COVID virus (viral RNA) in stool samples from children with multisystem inflammatory syndrome (a rare but serious condition that often strikes around four weeks after catching COVID) as well as spike protein and a marker of gut leakiness in their blood.”
Long COVID—also known as long-haul COVID, post-COVID-19, or its technical name, post-acute sequelae of COVID-19 or PASC—can involve health problems continuing weeks, months, or even years after a positive diagnosis, according to the federal Centers for Disease Control and Prevention (CDC).
Symptoms of long COVID, according to the researchers, include:
fatigue,
loss of smell,
memory loss,
gastrointestinal distress, and
shortness of breath.
“If someone could somehow get to that viral load and eliminate it, it might lead to resolution of symptoms,” Walt told the Boston Globe, which noted that the researchers may explore a clinical trial involving antiviral drugs for treatment of long COVID-19.
Clues from Earlier Studies on Long COVID-19
Medical conditions that persisted following a COVID-19 infection have been studied for some time. In fact, in an earlier study, Walt and others found children who developed a multisystem inflammation syndrome weeks after being infected by SARS-CoV-2, according to their 2021 paper published in The Journal of Clinical Investigation, titled, “Multisystem Inflammatory Syndrome in Children Is Driven by Zonulin-Dependent Loss of Gut Mucosal Barrier.”
Although these earlier studies provided clues, the cause of PASC remains unclear, the researchers noted. They planned to take a more precise look at PASC biology by using appropriate sampling and patient recruitment.
“Disentangling the complex biology of PASC will rely on the identification of biomarkers that enable classification of patient phenotypes. Here, we analyze plasma samples collected from PASC and COVID-19 patients to determine the levels of SARS-CoV-2 antigens and cytokines and identify a blood biomarker that appears in the majority of PASC patients,” the researchers wrote.
Finding a Marker of a Persistent Infection
The researchers used plasma samples from 63 people with a previous SARS-CoV-2 diagnosis (37 also had PASC), Medical News Today reported. Over a 12-month period, the researchers’ findings included:
Detection in 65% of PASC samples of full-length spike, S1 spike, and nucleocapsid throughout the year of testing.
Spike detected in 60% of PASC patient samples, and not found in the COVID-19 samples.
In an interview with Scientific American, bioengineer Zoe Swank PhD, post-doctoral researcher, Brigham and Women’s Hospital, and co-author of the study, said, “Our main hypothesis is that the spike protein is not causing the symptoms, but it’s just a marker that is released because you still have infection of some cells with SARS-CoV-2.”
In that article, Swank shared the scientists’ intent to do more research involving hundreds of samples over the course of the COVID-19 pandemic from many hospitals and people.
COVID-19 Not the Only Virus That Hangs On
Having a long-haul COVID-19 marker is a “game-changer,” according to an infectious disease expert who was not involved in the study.
“There has not so far been a clear, objective marker that is measurable in the blood of people experiencing long COVID-19,” Michael Peluso, MD, Assistant Professor, Medicine, University of California San Francisco, told Scientific American. “I hope their findings will hold up. It really would make a difference for a lot of people if a marker like this could be validated,” he added.
However, COVID-19 is not the only virus that could persist. Ebola also may linger in areas that skirt the immune system, such as the eye interior and central nervous system, according to a World Health Organization fact sheet.
Thus, medical laboratory leaders may want to follow the Brigham and Women’s Hospital research to see if the scientists validate their finding, discover a biomarker for long-haul COVID-19, and pursue a clinical trial for antiviral drugs. Such discoveries could have implications for how diagnostic professionals work with physicians to care for long COVID patients.
DeepMind hopes its unrivaled collection of data, enabled by artificial intelligence, may advance development of precision medicines, new medical laboratory tests, and therapeutic treatments
‘Tis the season for giving, and one United Kingdom-based artificial intelligence (AI) research laboratory is making a sizeable gift. After using AI and machine learning to create “the most comprehensive map of human proteins,” in existence, DeepMind, a subsidiary of Alphabet Inc. (NASDAQ:GOOGL), parent company of Google, plans to give away for free its database of millions of protein structure predictions to the global scientific community and to all of humanity, The Verge reported.
Pathologists and clinical laboratory scientists developing proteomic assays understand the significance of this gesture. They know how difficult and expensive it is to determine protein structures using sequencing of amino acids. That’s because the various types of amino acids in use cause the [DNA] string to “fold.” Thus, the availability of this data may accelerate the development of more diagnostic tests based on proteomics.
“For decades, scientists have been trying to find a method to reliably determine a protein’s structure just from its sequence of amino acids. Attraction and repulsion between the 20 different types of amino acids cause the string to fold in a feat of ‘spontaneous origami,’ forming the intricate curls, loops, and pleats of a protein’s 3D structure. This grand scientific challenge is known as the protein-folding problem,” a DeepMind statement noted.
Enter DeepMind’s AlphaFold AI platform to help iron things out. “Experimental techniques for determining structures are painstakingly laborious and time consuming (sometimes taking years and millions of dollars). Our latest version [of AlphaFold] can now predict the shape of a protein, at scale and in minutes, down to atomic accuracy. This is a significant breakthrough and highlights the impact AI can have on science,” DeepMind stated.
Release of Data Will Be ‘Transformative’
In July, DeepMind announced it would begin releasing data from its AlphaFold Protein Structure Database which contains “predictions for the structure of some 350,000 proteins across 20 different organisms,” The Verge reported, adding, “Most significantly, the release includes predictions for 98% of all human proteins, around 20,000 different structures, which are collectively known as the human proteome. By the end of the year, DeepMind hopes to release predictions for 100 million protein structures.”
According to Edith Heard, PhD, Director General of the European Molecular Biology Laboratory (EMBL), the open release of such a dataset will be “transformative for our understanding of how life works,” The Verge reported.
“I see this as the culmination of the entire 10-year-plus lifetime of DeepMind,” company CEO and co-founder Demis Hassabis (above), told The Verge. “From the beginning, this is what we set out to do: to make breakthroughs in AI, test that on games like Go and Atari, [and] apply that to real-world problems, to see if we can accelerate scientific breakthroughs and use those to benefit humanity.” The release of DeepMind’s entire protein prediction database will certainly do that. Clinical laboratory scientists worldwide will have free access to use it in developing new precision medicine treatments based on proteomics. (Photo copyright: BBC.)
Free Data about Proteins Will Accelerate Research on Diseases, Treatments
Research into how protein folds and, thereby, functions could have implications to fighting diseases and developing new medicines, according to DeepMind.
“This will be one of the most important datasets since the mapping of the human genome,” said Ewan Birney, PhD, Deputy Director General of the EMBL, in the DeepMind statement. EMBL worked with DeepMind on the dataset.
DeepMind protein prediction data are already being used by scientists in medical research. “Anyone can use it for anything. They just need to credit the people involved in the citation,” said Demis Hassabis, DeepMind CEO and Co-founder, in The Verge.
In a blog article, Hassabis listed several projects and organizations already using AlphaFold. They include:
“As researchers seek cures for diseases and pursue solutions to other big problems facing humankind—including antibiotic resistance, microplastic pollution, and climate change—they will benefit from fresh insights in the structure of proteins,” Hassabis wrote.
Because of the deep financial backing that Alphabet/Google can offer, it is reasonable to predict that DeepMind will make progress with its AI technology that regularly adds capabilities and accuracy, allowing AlphaFold to be effective for many uses.
This will be particularly true for the development of new diagnostic assays that will give clinical laboratories better tools for diagnosing disease earlier and more accurately.
