Should their research result in new ways to identify and diagnose disease, doctors and clinical laboratories would do confirmatory testing and then initiate a precision medicine plan.
Dan Roden, MD, Senior Vice President for Personalized Medicine at VUMC and Senior Author of the Circulation study, said in a VUMC news release that the findings support the growing use of genetic information in clinical care.
“The questions we asked were: How many people who had no previous indication for cardiac genetic testing had pathogenic or likely pathogenic variants, and how many of those people actually had a phenotype in the electronic health records?” he explained.
Arrhythmia More Common than Previously Thought
The VUMC researchers drew data for their reports from the eMERGE Phase III study, which investigated the feasibility of population genomic screening by sequencing 109 genes across the spectrum of Mendelian diseases—genetic diseases that are caused by a mutation in a single gene—in more than 20,000 individuals. The scientists returned variant results to the participants and used EHR and follow-up clinical data to ascertain patient phenotypes, according to a Northwestern University Feinberg School of Medicine news release.
The research team looked specifically at the 120 consortium participants that had disease-associated pathogenic or likely pathogenic (P/LP) variants in the arrhythmia-associated genes. An analysis of the EHR data showed that 0.6% of the studied population had a variant that increases risk for potentially life-threatening arrhythmia, and that there was overrepresentation of arrhythmia phenotypes among patients, the VUMC news release noted.
The research team returned results to 54 participants and, with clinical follow-up, made 19 diagnoses (primarily long-QT syndrome) of inherited arrhythmia syndromes. Twelve of those 19 diagnoses were made only after variant results were returned, the study’s authors wrote.
Carlos G. Vanoye, PhD, Research Associate Professor of Pharmacology at Northwestern University (NU), said the study suggests arrhythmia genes may be more common than previously thought.
“A person can carry a disease-causing gene variant but exhibit no obvious signs or symptoms of the disease,” he said in the NU news release. “Because the genes we studied are associated with sudden death, which may have no warning signs, discovery of a potentially life-threatening arrhythmia gene variant can prompt additional clinical work-up to determine risks and guide preventive therapies.”
“The take-home message is that 3% of people will carry a pathogenic or likely pathogenic variant in a disease-causing gene and many others will carry variants of uncertain significance,” said Dan Roden, MD (above), Senior Vice President for Personalized Medicine at VUMC and Senior Author of the Circulation study in the VUMC news release. “We can use genetic testing, electronic health record phenotypes, and in vitro technologies to evaluate and find people who have unrecognized genetic disease and save lives by making earlier diagnoses.” Clinical laboratories will play a key role in making those early diagnoses and in managing personalized medical treatment plans. (Photo copyright: Vanderbilt University.)
Variants of Uncertain Significance
According to the NU news release, the scientists determined the functional consequences of the variants of uncertain significance they found and used that data to refine the assessment of pathogenicity. In the end, they reclassified 11 of the variants: three that were likely benign and eight that were likely pathogenic.
In the JAMA Oncology study, the VUMC scientists and other researchers conducted a phenome-wide association study to find EHR phenotypes associated with variants in 23 hereditary cancer genes. According to the VUMC news release, they identified 19 new associations:
The VUMC study findings could improve disease diagnosis and management for cancer patients and help identify high-risk individuals, the researchers noted in their published report.
In an editorial published in Circulation, titled, “First Steps of Population Genomic Medicine in the Arrhythmia World: Pros and Cons,” the professors noted that using genomic information in the case of potentially lethal inherited arrhythmia syndromes could be “lifesaving,” but questioned the benefits of reporting such secondary findings when patients are undergoing genome sequencing for other indications such as cancer.
“The likelihood that these ‘genetic diagnoses’ are translated into clinical diagnoses have not been completely evaluated,” they wrote. “In addition to the challenge of accurately identifying disease-causing genetic variants, defining the penetrance of such variants is critical to this process, i.e., what proportion of individuals in the general population with apparently pathogenic variants will develop the associated phenotype? If penetrance is low for particular gene/phenotype combinations, the costs associated with clinical screening and the psychological effects on individuals informed that they have potentially life-threatening variants may outweigh the benefits of the few new clinical diagnoses.”
These latest studies provide further evidence of the value of big data in healthcare and offer another lesson to clinical laboratories and pathologist about the future role data streaming from clinical laboratories and pathology assays may have in the growth of personalized medicine.
As demand for DTC at-home genetic testing increases among consumers and healthcare professionals, clinical laboratories that offer similar assays may want to offer their own DTC testing program
Things are happening in the direct-to-consumer (DTC) medical laboratory testing market. Prior to the pandemic, the number of consumers interested in ordering their own diagnostic tests grew at a rapid rate. The SARS-CoV-2 outbreak, however, and the need for consumers to access COVID-19 tests, caused DTC test sales to skyrocket.
One company benefiting from the DTC trend is New York City-based LetsGetChecked. In March, it announced its acquisition of Veritas Genetics which included that company’s Veritas Intercontinental business division. No purchase price was disclosed.
LetsGetChecked describes itself as a “virtual care company that allows customers to manage their health from home, providing direct access to telehealth services, pharmacy, and [clinical] laboratory tests with at-home sample collection kits for a wide range of health conditions,” according to the company’s LinkedIn page.
“Through these acquisitions, LetsGetChecked will leverage the power of whole genome sequencing to launch a full lifecycle of personalized healthcare, delivering the most comprehensive health testing and care solution on the market,” said Peter Foley, Founder and CEO of LetsGetChecked in a press release.
“By integrating Veritas Genetics’ and Veritas Intercontinental’s capabilities with LetsGetChecked’s scalable diagnostic and virtual care infrastructure, we are able to turn comprehensive genetic insights into practical recommendations and lifestyle changes, guided by clinical experts,” he added.
“Our mission to deliver the benefits of whole genome sequencing to millions of individuals continues as part of the LetsGetChecked family. I am particularly excited about the opportunity to combine genetic testing with the broad spectrum of virtual and at-home care models offered by LetsGetChecked. I expect these acquisitions will change the future of personalized healthcare as we know it,” said geneticist George Church, PhD, co-founder of Veritas Genetics, and Professor of Health Sciences and Technology at Harvard and MIT, in a press release. (Photo copyright: Wyss Institute at Harvard University.)
Leveraging the Power of Whole Genome Sequencing
To date, LetsGetChecked claims it has delivered nearly three million at-home direct-to-consumer tests and served more than 300 corporate customers with testing services and biometric screening solutions since its founding in 2015.
The company focuses on manufacturing, logistics, and lab analysis in its CAP-accredited, CLIA-certified laboratory in Monrovia, Calif., as well as physician support, and prescription fulfillment. The DTC company’s products include at-home tests for women’s health, men’s health, basic wellness, sexual health, and SARS-CoV-2 testing.
Veritas Genetics also was a DTC testing company co-founded by internationally-known geneticist George Church, PhD. In 2016, the company announced it would deliver a whole human genome sequence (WGS) for just $999—breaking the $1,000 cost barrier for whole genome sequencing.
“There is no more comprehensive genetic test than your whole genome,” Rodrigo Martinez, former Veritas Chief Marketing and Design Officer, told CNBC. “So, this is a clear signal that the whole genome is basically going to replace all other genetic tests. And this [price drop] gets it closer and closer and closer.”
That market strategy did not succeed. By the end of 2019, the company announced it would cease operations in the United States but continue operations in Europe and Latin America. It has sought a buyer for the company since that time. Now, almost three years later, LetsGetChecked will become the new owner of Veritas Genetics.
Veritas’ primary product, myGenome was launched in 2018 as a whole genome sequencing and interpretation service to help consumers improve their health and increase longevity. The myGenome test screens for and provides insight on many hereditary diseases such as cancer, cardiovascular disease, and neurological disorders. It also provides observations on more than 50 personal traits and ancestry information.
In addition to bringing whole genome sequencing abilities to its test offerings for consumers, LetsGetChecked hopes the acquisitions will create new testing capabilities such as pharmacogenomics, cancer and viral screenings, and maternal fetal screenings.
“By integrating Veritas Genetics’ and Veritas Intercontinental’s genetics offering with our scalable virtual care infrastructure, we are able to leverage the power of whole genome sequencing to launch a full lifecycle of personalized healthcare, which has always been our goal,” Foley told MobiHealthNews.
Veritas Genetics and Veritas Intercontinental will continue to operate under the LetsGetChecked family of companies.
BioIQ also Acquired by LetsGetChecked
In early May, LetsGetChecked also acquired diagnostic testing and health improvement technology company BioIQ, which will continue to operate as a wholly-owned subsidiary.
BioIQ offers at-home tests, health screenings, and vaccinations to consumers. The company’s products include:
Heart health panel,
Lipid panel,
Respiratory panel,
Prevention panel, and
Wellness panel.
Individual tests offered by BioIQ include:
A1C,
COVID-19,
Hepatitis C test and
Sexually transmitted diseases.
BioIQ also offer e-vouchers for health screenings and vaccinations at participating retail pharmacies, clinical laboratories, and physician’s offices.
“The future of healthcare is in providing high-quality at-home diagnostics and care that comprehensively serve an individual’s health needs throughout their whole life,” said Foley in a press release about the BioIQ acquisition. “With this acquisition, LetsGetChecked gains a trusted partner with an extensive knowledge base and a breadth of experience in serving health plans and employer markets to deliver healthcare solutions at scale.”
These acquisitions by LetsGetChecked demonstrate how genetic testing companies are pivoting to new strategies. Clinical laboratories that perform genetic testing will want to monitor how these partnerships unfold in the future as healthcare consumers and providers continue to embrace at-home genetic testing.
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.
Given the large number of mutations found in the SARS-CoV-2 Omicron variant, experts in South Africa speculate it likely evolved in someone with a compromised immune system
As the SARS-CoV-2 Omicron variant spreads around the United States and the rest of the world, infectious disease experts in South Africa have been investigating how the variant developed so many mutations. One hypothesis is that it evolved over time in the body of an immunosuppressed person, such as a cancer patient, transplant recipient, or someone with uncontrolled human immunodeficiency virus infection (HIV).
One interesting facet in the story of how the Omicron variant was being tracked as it emerged in South Africa is the role of several medical laboratories in the country that reported genetic sequences associated with Omicron. This allowed researchers in South Africa to more quickly identify the growing range of mutations found in different samples of the Omicron virus.
“Normally your immune system would kick a virus out fairly quickly, if fully functional,” Linda-Gail Bekker, PhD, of the Desmond Tutu Health Foundation (formerly the Desmond Tutu HIV Foundation) in Cape Town, South Africa, told the BBC.
“In someone where immunity is suppressed, then we see virus persisting,” she added. “And it doesn’t just sit around, it replicates. And as it replicates it undergoes potential mutations. And in somebody where immunity is suppressed that virus may be able to continue for many months—mutating as it goes.”
Multiple factors can suppress the immune system, experts say, but some are pointing to HIV as a possible culprit given the likelihood that the variant emerged in sub-Saharan Africa, which has a high population of people living with HIV.
Li “was among the first to detail extensive coronavirus mutations in an immunosuppressed patient,” the LA Times reported. “Under attack by HIV, their T cells are not providing vital support that the immune system’s B cells need to clear an infection.”
Linda-Gail Bekker, PhD (above), of the Desmond Tutu Health Foundation cautions that these findings should not further stigmatize people living with HIV. “It’s important to stress that people who are on anti-retroviral medication—that does restore their immunity,” she told the BBC. (Photo copyright: Test Positive Aware Network.)
Omicron Spreads Rapidly in the US
Genomics surveillance Data from the CDC’s SARS-CoV-2 Tracking system indicates that on Dec. 11, 2021, Omicron accounted for about 7% of the SARS-CoV-2 variants in circulation, the agency reported. But by Dec. 25, the number had jumped to nearly 60%. The data is based on sequencing of SARS-CoV-2 by the agency as well as commercial clinical laboratories and academic laboratories.
Experts have pointed to several likely factors behind the variant’s high rate of transmission. The biggest factor, NPR reported, appears to be the large number of mutations on the spike protein, which the virus uses to attach to human cells. This gives the virus an advantage in evading the body’s immune system, even in people who have been vaccinated.
“The playing field for the virus right now is quite different than it was in the early days,” Joshua Schiffer, MD, of the Fred Hutchinson Cancer Research Center, told NPR. “The majority of variants we’ve seen to date couldn’t survive in this immune environment.”
One study from Norway cited by NPR suggests that Omicron has a shorter incubation period than other variants, which would increase the transmission rate. And researchers have found that it multiplies more rapidly than the Delta variant in the upper respiratory tract, which could facilitate spread when people exhale.
Using Genomics Testing to Determine How Omicron Evolved
But how did the Omicron variant accumulate so many mutations? In a story for The Atlantic, virologist Jesse Bloom, PhD, Professor, Basic Sciences Division, at the Fred Hutchinson Cancer Research Center in Seattle, described Omicron as “a huge jump in evolution,” one that researchers expected to happen “over the span of four or five years.”
Hence the speculation that it evolved in an immunosuppressed person, perhaps due to HIV, though that’s not the only theory. Another is “that the virus infected animals of some kind, acquired lots of mutations as it spread among them, and then jumped back to people—a phenomenon known as reverse zoonosis,” New Scientist reported.
Still, experts are pointing to emergence in someone with a weakened immune system as the most likely cause. One of them, the L.A. Times reported, is Tulio de Oliveira, PhD, Affiliate Professor in the Department of Global Health at the University of Washington. Oliveira leads the Centre for Epidemic Response and Innovation at Stellenbosch University in South Africa, as well as the nation’s Network for Genomic Surveillance.
The Network for Genomic Surveillance, he told The New Yorker, consists of multiple facilities around the country. Team members noticed what he described as a “small uptick” in COVID cases in Gauteng, so on Nov. 19 they decided to step up genomic surveillance in the province. One private clinical laboratory in the network submitted “six genomes of a very mutated virus,” he said. “And, when we looked at the genomes, we got quite worried because they discovered a failure of one of the probes in the PCR testing.”
Looking at national data, the scientists saw that the same failure was on the rise in PCR (Polymerase chain reaction) tests, prompting a request for samples from other medical laboratories. “We got over a hundred samples from over thirty clinics in Gauteng, and we started genotyping, and we analyzed the mutation of the virus,” he told The New Yorker. “We linked all the data with the PCR dropout, the increase of cases in South Africa and of the positivity rate, and then we began to see it might be a very suddenly emerging variant.”
Oliveira’s team first reported the emergence of the new variant to the World Health Organization, on Nov. 24. Two days later, the WHO issued a statement that named the newly classified Omicron variant (B.1.1.529) a “SARS-CoV-2 Variant of Concern.”
Microbiologists and clinical laboratory specialists in the US should keep close watch on Omicron research coming out of South Africa. Fortunately, scientists today have tools to understand the genetic makeup of viruses that did not exist at the time of SARS 2003, Swine flu 2008/9, MERS 2013.
Teams from multiple Swedish organizations are investigating the relationship of protein-coding genes to antibodies
Scientists in Sweden are discovering new ways to map the expression of genes in cells, tissues, and organs within the human body thanks to advances in molecular profiling. Their study has successfully combined the analysis of single-cell transcriptomics with spatial antibody-based protein profiling to produce a high-resolution, single-cell mapping of human tissues.
The data links protein-coding genes to antibodies, which could help researchers develop clinical laboratory tests that use specific antibodies to identify and target infectious disease. Might this also lead to a new menu of serology tests that could be used by medical laboratories?
This research is another example of how various databases of genetic and proteomic information—different “omics”—are being combined to produce new understanding of human biology and physiology.
In a Human Protein Atlas (HPA) project press release, Director of the HPA consortium and Professor of Microbiology at Royal Institute of Technology in Stockholm, Mathias Uhlén, PhD, said, “The [Science Advances] paper describes an important addition to the Human Protein Atlas (HPA) which has become one of the world’s most visited biological databases, harboring millions of web pages with information about all the human protein coding genes.”
“We are excited that the new open-access Single Cell Type section constitutes a unique resource for studying the cell type specificity and exact spatial localization of all our proteins”, said Cecilia Lindskog, PhD (above), Head of the HPA Tissue Atlas and Associate Professor, Experimental Pathology, Uppsala University, in the Protein Atlas press release. Medical laboratories may soon have new serology tests to perform that were developed based on HPA data. (Photo copyright: Human Uterus Cell Atlas.)
Distinct Expression Clusters Consistent to Similar Cell Types
To perform their research, the scientists mapped the gene expression profile of all protein-coding genes across different cell types. Their analysis showed that there are distinct expression clusters which are consistent to cell types sharing similar functions within the same organs and between organs of the human body.
The scientists examined data from non-diseased human tissues and organs using three main criteria:
Publicly available raw data from human tissues containing good technical quality with at least 4,000 cells analyzed and at least 20 million read counts by the sequencing for each tissue.
High correlation between pseudo-bulk transcriptomics profile from the scRNA-Seq data and bulk RNA-Seq generated as part of the Human Protein Atlas (HPA).
High correlation between the cluster-specific expression and the expected expression pattern of an extensive selection of marker genes representing well-known tissue- and cell type-specific markers, including both markers from the original publications and additional markers used in pathology diagnostics.
According to the HPA press release, “across all analyzed cell types, almost 14,000 genes showed an elevated expression in particular cell types, out of which approximately 2,000 genes were found to be specific for only one of the cell types.”
The press release also states, “cell types in testis showed the highest numbers of cell type elevated genes, followed by ciliated cells. Interestingly, only 11% of the genes were detected in all analyzed cell types suggesting that the number of essential genes (‘house-keeping’) are surprisingly few.”
Omics-based Biomarkers for Accurate Diagnosis of Disease
The Human Protein Atlas is the largest and most comprehensive database for spatial distribution of proteins in human tissues and cells. It provides a valuable tool for researchers who study and analyze protein localization and expression in human tissues and cells.
Ongoing improvements in gene sequencing technologies are making research of genes more accurate, faster, and more economical. Advances in gene sequencing also could help medical professionals discover more personalized care for patients leading to improved outcomes. A key goal of precision medicine.
One of the conclusions to be drawn from this work is that clinical laboratories and anatomic pathology groups will need to be able to handle immense amounts of data, while at the same time having the capabilities to analyze that data and identify useful patterns that can help diagnose patients earlier and more accurately.
