Since the early 1980s, UBC’s CMPT program, led by medical microbiologist Michael Noble, MD, has provided external quality assessment (EQA) for clinical microbiology and water testing laboratories. This includes providing biological samples related to:
“Typical of every jurisdiction in North America and probably around the world, BCCDC got swamped beyond swamped,” said Noble, the Clinical Microbiology Proficiency Testing (CMPT) program’s first and current Chair, in an exclusive interview with Dark Daily. “The increase was 10-fold, and they were unable to provide all the services they wanted to do. And since I was already running a proficiency testing program across the province, they asked if I would provide that service for COVID-19 for laboratories that were doing the testing.”
Michael Noble, MD (above), is Professor Emeritus (active) in UBC’s Department of Pathology and Laboratory Medicine and Chair of the Program Office for Laboratory Quality Management (POLQM). He began his career as a medical microbiologist but soon focused on laboratory quality management. Within the Department of Pathology and Laboratory Medicine, Noble co-developed the Clinical Microbiology Proficiency Testing (CMPT) program in 1983, a program he still chairs but will soon pass on to a new leader. (Photo copyright: University of British Columbia.)
CMPT’s Proficiency Testing Serves Labs Worldwide
UBC’s CMPT external quality assessment (EQA) program serves all medical laboratories in British Columbia, as well as other labs in Canada, Europe, South America, and the Caribbean. Just over 200 laboratories currently participate in the program. More labs participated in past years, before lab consolidation affected CMPT and other programs as well, Noble said.
CMPT’s proficiency testing ensures that participant laboratories that have been provided with simulated samples can perform tests at the “level of quality and competence required,” notes UBC’s CMPT website.
“Samples are complex, highly realistic, and clinically relevant. CMPT samples contain host elements as well as targeted pathogens,” Noble explained on his blog, “Making Medical Laboratory Quality Relevant.”
COVID-19 Brings Non-Traditional ‘Laboratories’ to CMPT’s Proficiency Testing Program
UBC’s proficiency testing for SARS-CoV-2, the coronavirus that causes the COVID-19 infection, differs from other CMPT programs. That’s due to new participants that entered the laboratory testing program during the COVID-19 pandemic that are performing COVID-19 testing in non-traditional locations, Noble stated.
“In our proficiency programs, we had mainly been dealing with traditional clinical laboratories,” Noble explained. “But now, we find people doing COVID-19 testing—even though defined as medical laboratories—who are working in airports, or in tourism, or the movie industry, or forestry. They may never have worked in an actual clinical laboratory. So, it’s a very different style of proficiency testing. There has been a lot of handholding, teleconferences, discussions, and one-on-ones with that group,” Noble said.
Participant laboratories receive viral material that “simulates typical samples.” They need to demonstrate proficiency by performing the test and reporting it as positive, negative, or inconclusive.
“Our product is derived from a pure culture of a single strain of SARS-CoV-2, and it appears to be effective for all targets,” Noble stated.
Detecting COVID-19 by Gargling and Rinsing
UBC’s program typically offers simulated sampling for detection of SARS-CoV-2 in nasopharyngeal swabs. However, the BC Center for Disease Control’s (BCCDC) mouth rinse and gargle sample collection for diagnosis of COVID-19 also is available and widely used in Canada, Noble said.
In his career, Noble transitioned from medical microbiology to qualitology, which he describes as “the study of quality in the medical laboratory.”
In stressing the importance of laboratory quality testing, Noble describes the possibility of laboratory testing going awry and leading to a microbiological public health emergency.
“What happens if there’s a stool sample, and someone misses the presence of Campylobacteriosis in the stool? What happens if that’s part of a foodborne disease and there’s an outbreak in the city and samples are being missed? How many people will be impacted as a result of that error?” he asked.
University of British Columbia Endows a Chair for Laboratory Quality Management
Noble says UBC’s Program Office for Laboratory Quality Management (POLQM) has involved organizations worldwide and certified more than 500 people.
“The impact they have over their laboratories has been huge. Maybe that would have happened without us. But we were a part of that. And our impact is not one laboratory or one city or one province but widespread, and that’s a real and enriching experience to have,” he said.
But now it is time for him to move on. Noble secured (through UBC), a benefactor to establish the endowed Chair for Laboratory Quality Management. The family of the late Donald B. Rix, MD, a Canadian pathologist and philanthropist, gave $1.5 million (matched by the university) to create the Associate Professor (Grant Tenure) Donald B. Rix Professorship in Laboratory Quality at UBC, Department of Pathology and Laboratory Medicine.
Long-serving pathologists and medical laboratory professionals may remember that Rix was the founder and chair of MDS Metro Laboratory Services (now known as LifeLabs Medical Laboratory Services). It grew into the largest private medical laboratory in Western Canada.
Referring to this endowed new Chair for Laboratory Quality Management, Noble said, “I think this is the first named position of laboratory quality in North America.” UBC has commenced reviewing applications for the position, which is expected to be effective in January 2022. Pathologists and clinical laboratory scientists with appropriate qualifications and interest in this position should contact Dr. Noble’s office at the University of British Columbia Faculty of Medicine.
VCU scientists used the technique to measure mutations associated with acute myeloid leukemia, potentially offering an attractive alternative to DNA sequencing
More accurate but less-costly cancer diagnostics are the Holy Grail of cancer research. Now, research scientists at Virginia Commonwealth University (VCU) say they have developed a clinical laboratory diagnostic technique that could be far cheaper and more capable than standard DNA sequencing in diagnosing some diseases. Their method combines digital polymerase chain reaction (dPCR) technology with high-speed atomic force microscopy (HS-AFM) to generate nanoscale-resolution images of DNA.
The technique allows the researchers to measure polymorphisms—variations in gene lengths—that are associated with many cancers and neurological diseases. The VCU scientists say the new technique costs less than $1 to scan each dPCR reaction.
“We chose to focus on FLT3 mutations because they are difficult to [diagnose], and the standard assay is limited in capability,” said physicist Jason Reed, PhD, Assistant Professor in the Virginia Commonwealth University Department of Physics, in a VCU press release.
Reed is an expert in nanotechnology as it relates to biology and medicine. He led a team that included other researchers in VCU’s physics department as well as physicians from VCU Massey Cancer Center and the Department of Internal Medicine at VCU School of Medicine.
“The technology needed to detect DNA sequence rearrangements is expensive and limited in availability, yet medicine increasingly relies on the information it provides to accurately diagnose and treat cancers and many other diseases,” said Jason Reed, PhD (above center, with Andrey Mikheikin, PhD, on left and Sean Koebley, PhD, on right), in a press release from Virginia Commonwealth University (VCU). “We’ve developed a system that combines a routine laboratory process with an inexpensive yet powerful atomic microscope that provides many benefits over standard DNA sequencing for this application, at a fraction of the cost.” (Photo copyright: Virginia Commonwealth University.)
Validating the Clinical Laboratory Test
The physicists worked with two VCU physicians—hematologist/oncologist Amir Toor, MD, and hematopathologist Alden Chesney, MD—to compare the imaging technique to the LeukoStrat CDx FLT3 Mutation Assay, which they described as the “current gold standard test” for diagnosing FLT3 gene mutations.
The researchers said their technique matched the results of the LeukoStrat test in diagnosing the mutations. But unlike that test, the new technique also can measure variant allele frequency (VAL). This “can show whether the mutation is inherited and allows the detection of mutations that could potentially be missed by the current test,” states the VCU press release.
“We plan to continue developing and testing this technology in other diseases involving DNA structural mutations,” Reed said. “We hope it can be a powerful and cost-effective tool for doctors around the world treating cancer and other devastating diseases driven by DNA mutations.”
“In our approach we first used digital PCR, in which a mixed sample is diluted to less than one target molecule per aliquot and the aliquots are amplified to yield homogeneous populations of amplicons,” he said. “Then, we deposited each population onto an atomically-flat partitioned surface.”
The VCU researchers “scanned each partition with high-speed atomic force microscopy, in which an extremely sharp tip is rastered across the surface, returning a 3D map of the surface with nanoscale resolution,” he said. “We wrote code that traced the length of each imaged DNA molecule, and the distribution of lengths was used to determine whether the aliquot was a wild type [unmutated] or variant.”
In Diagnostics World, Reed said the method “doesn’t really have any more complexity than a PCR assay itself. It can easily be done by most lab technicians.”
Earlier Research
A VCU press release from 2017 noted that Reed’s research team had developed technology that uses optical lasers (similar to those in a DVD player) to accelerate the scanning. The researchers previously published a study about the technique in Nature Communications, and a patent is currently pending.
“DNA sequencing is a powerful tool, but it is still quite expensive and has several technological and functional limitations that make it difficult to map large areas of the genome efficiently and accurately,” Reed said in the 2017 VCU press release. “Our approach bridges the gap between DNA sequencing and other physical mapping techniques that lack resolution. It can be used as a stand-alone method or it can complement DNA sequencing by reducing complexity and error when piecing together the small bits of genome analyzed during the sequencing process.”
Using CRISPR technology, the team also developed what they described as a “chemical barcoding solution,” placing markers on DNA molecules to identify genetic mutations.
New DNA Clinical Laboratory Testing?
Cancer diagnostics are constantly evolving and improving. It is not clear how long it will be before VCU’s new technique will reach clinical laboratories that perform DNA testing, if at all. But VCU’s new technique is intriguing, and should it prove viable for clinical diagnostic use it could revolutionize cancer diagnosis. It is a development worth watching.
Physician use of genetic tests continues to grow at robust rates, even during the pandemic, but uncertainty about managed care reimbursement hangs over the market
It may surprise many pathologists and clinical laboratory managers to learn that the market for genetic testing is robust and growing swiftly, even in the midst of the COVID-19 pandemic. At the same time, the explosion in both the number of unique genetic tests available to physicians, and the willingness of doctors to order genetic tests for their patients, are creating major challenges for both government and private payers.
Moreover, how payers are attempting to gain control over this boom in genetic testing is creating serious problems for genetic testing companies seeking reimbursement for their test claims. This is because health insurers are taking aggressive steps to control their spending on genetic tests. Some of those steps include:
Prior-authorization requirements for an ever-larger number of genetic tests.
Reducing the prices paid for high-cost genetic tests.
Tough audits that use sampling and extrapolation and produce sizeable recoupment demands.
Unexpected Developments in Genetic Test Marketplace
These are reasons why clinical laboratories need to fully understand the state of the genetic testing market. Physicians are receptive to ordering genetic tests that will improve the care they provide their patients. But health insurers want better control over the unplanned and substantial increases in the total amount of money they pay out for the surging number of genetic test claims.
Collectively, these developments confront genetic testing companies with a mix of good news and bad news. The good news is that more physicians are using genetic tests in their daily medical practice. The bad news is that many payers are erecting ever-more restrictive hurdles that labs must overcome when submitting genetic test claims and seeking adequate payment.
Strategic Insights into What’s Changing with Genetic Testing
This webinar will be one of the most important strategic assessments of genetic testing presented to the clinical laboratory and diagnostics industries since the COVID-19 pandemic began last March. Your presenters are recognized thought-leaders in the genetic testing and laboratory medicine industries. Speaking in order are:
Bruce Quinn, MD, PhD, Principal, Bruce Quinn Associates LLC, Los Angeles: An expert in how Medicare and private payers establish coverage guidelines and prices for new genetic tests, Dr. Quinn will explain the key differences in how private payers are managing genetic test utilization and payment, compare to the federal Medicare program.
Heather Agostinelli, Asst. Vice President, Strategic Revenue Operations, XIFIN Inc., San Diego: Heather will provide a detailed perspective on the daily actions by payers as they process claims and issue payment for genetic tests. She will also present recommendations for how labs can optimize the number of clean genetic test claims, thus helping shorten payment times in ways that improve cash flow.
Rob Metcalf, CEO, Concert Genetics, Nashville, Tenn.: He will discuss the scope and scale of the explosion in the number of genetic test claims by sharing data, charts, and analyses usually only available to clients.
Your Chair and Moderator will be Robert L. Michel, Editor-in-Chief of The Dark Report.
The purpose of the upcoming webinar includes helping attendees with the following and more:
Learn why payers must now deal with more than 1,000 new genetic testing products launching every month and how that complicates claims processing.
Understand how the variation in CPT coding by different genetic testing labs complicates claims processing by payers.
Learn why “benefit investigation” is already a huge factor as consumers seek the lab with the cheapest genetic test price before they agree to be tested.
Master the art of working with prior authorization programs and know why having documents prior to authorization still does not necessarily mean the payer will reimburse for a genetic test claim.
Understand Medicare’s policy changes at the national level for genetic tests.
Know the core elements of the Medicare MolDx program that gov-erns genetic test claims across 28 states.
Valuable Information for Financial Analysis, Managed Care Executives
In addition to bringing clinical pathologists and directors/managers of clinical laboratories up to date on the genetic testing marketplace, this webinar will provide valuable insights into financial analysts’ tracking of genetic testing companies, managed care executives’ handling of genetic testing claims, genetic counselors, and others involved in managing clinical service lines that utilize genetic tests in patient care.
Medical technologists and clinical laboratory professionals are the unsung heroes of the COVID-19 pandemic and the public is beginning to notice
Medical technologists (MTs) and clinical laboratory scientists (CLSs) are the foundation of every successful clinical laboratory. But they seldom make the news. Therefore, it is worth noting, during this COVID-19 pandemic, when clinical laboratory professionals receive public recognition for the important role they play in fighting the disease.
A news story published by the Canadian Broadcasting Corporation (CBC), titled, “Lab Tech Who Found B.C.’s 1st Case of COVID-19 Recalls ‘Sheer Terror’ of Discovery,” describes a laboratory technologist’s experience in British Columbia when she discovered the Canadian province’s first positive case of COVID-19 in January of 2020.
Finding COVID-19 for the First Time
On January 27, 2020, Rebecca Hickman, Public Health Laboratory Technologist, Molecular Biology and Genomics at BC Centre for Disease Control (BCCDC) was carefully monitoring samples for COVID-19 and fearing a positive result for the SARS-CoV-2 coronavirus when her worst fear appeared before her eyes.
“I actually started to see it get positive within a few seconds,” Hickman recalled. “My first feeling was sheer terror, from a personal point of view.”
When Hickman realized a sample was going to test positive, she called Tracy Lee, Technical Coordinator at BC Centre for Disease Control and co-designer of the BCCDC’s COVID-19 test. Hickman had to interrupt Lee in a meeting, who then hurried to the lab to watch the test complete. It was a definite positive, the first confirmed case in British Columbia.
“To design, validate, and implement a molecular laboratory test usually takes months if not years, and so to do that in the span of days is a huge achievement,” Hickman told the CBC.
The following day, it was announced to the residents of BC that the COVID-19 coronavirus was in their province and that they needed to start taking necessary precautions. “This is the first time in my life I’ve ever found things out before I read it in the news,” Hickman said.
Supply Shortages Challenge British Columbia Clinical Laboratories
Hickman noted there have been several challenges in dealing with COVID-19 over the past year. “The instability and craziness of it all has been the hardest part,” she said. Last spring, the BC lab, like most labs, had to deal with a shortage of supplies and personal protective equipment.
According to BC Centre for Disease Control (BCCDC) data, as of March 2, 2021, there have been 81,367 confirmed cases of COVID-19 in the province of British Columbia. A total of 75,255 of those individuals have recovered from the coronavirus, more than 300 patients remain hospitalized, and 1,365 British Columbians have perished due to COVID-19. The population of the western Canadian province is approximately 5.1 million.
Today, Hickman, spends a majority of her time in the laboratory doing whole genome sequencing of confirmed COVID-19 cases. The data she collects is used for outbreak response and for tracking new variants of the SARS-CoV-2 coronavirus that are appearing in different parts of the world. “It has been easily the most difficult year of my life, but also the most fulfilling,” she told the CBC. “What we have achieved here over the last year is huge.”
In their laboratory at the B.C. Centre for Disease Control in British Columbia, Canada, researchers Tracy Lee (above left) and Rebecca Hickman (above right) “are designing new tests to quickly identify variants of the COVID-19 virus,” North Shore News (NSN) reported. Now, wrote NSN, “the pair are working on a new type of ‘rapid test’ that will be able to detect ‘variants of concern’—particularly the U.K., South African, and Brazilian variants—at the same time as determining if a test is positive for COVID-19. When it’s finalized, that test is expected to dramatically speed up the process of hunting the variants.” (Photo copyright: North Shore News.)
Clinical Laboratories on the Front Lines
Last year, the American Society for Clinical Pathology (ASCP) produced a docuseries titled, “Laboratories on the Front Lines: Battling COVID-19” which highlighted the critical work clinical laboratories are doing to care for patients during the SARS-CoV-2 pandemic. The five-part series interviewed medical laboratory professionals across the US about their experiences during the pandemic.
In one episode, Stephanie Horiuchi, Clinical Microbiology Specialist at UCLA Health Systems, discussed how challenging and rewarding it has been working on the pandemic.
“Very long days. I’m not going to lie. Very, very long days, but it’s rewarding. I know the importance of what I am doing, and I know the importance of what needs to be done,” she said. “So, the time that I am here, it does go by very fast. You look up at the clock and you’re like oh, its 9pm. And then when I go home, it’s just eat and go to sleep and then rinse and repeat.
“I feel that this is a really important area of work that we all do as microbiologists,” Horiuchi continued. “And to just serve patients every day and to know that I am helping someone, it really warms my soul.”
In another episode of the docuseries, Professor of Pathology and Laboratory Medicine Alyssa Ziman, MD, Division Chief, Clinical Laboratory Medicine at UCLA Health, was interviewed regarding how they are coping with the increased demand for medical laboratory services.
“It’s been a really difficult and challenging time for our health system, for our laboratories, for our staff that are working through to provide the best possible patient care,” she said. Ziman is also Medical Director, Transfusion Medicine, at UCLA Health and Medical Director, Clinical Laboratories, at Ronald Reagan UCLA Medical Center. “Every day is a new challenge and a new way to adapt to changing rules from the CDC and from the LA County Public Health Department and to really evolve, so that we can continue to provide the testing that we have and continue to support our staff and our patients.”
Unsung Heroes of COVID-19
The COVID-19 pandemic has placed a strain on medical resources throughout the world. Clinical laboratory professionals are emerging as the unsung heroes of the crisis and the entire medical laboratory profession is receiving much deserved positive recognition for the crucial role laboratories are playing in fighting the pandemic.
The merger is expected to boost investment in 23andMe’s consumer health and therapeutics businesses
After years of spectacular growth, the popularity of direct-to-consumer (DTC) genetic testing is beginning to wane. Nevertheless, opportunities still exist in the DTC genetic testing market for visionaries with funds to invest.
One such visionary is billionaire Richard Branson, founder of the multinational venture capital conglomerate Virgin Group (VG). Branson’s VG Acquisition Corp. (NYSE:VGAC), a special purpose acquisition company (SPAC), announced it is merging with 23andMe of Sunnyvale, Calif., to create a publicly-traded company with the New York Stock Exchange ticker symbol ME.
In a VG press release, Branson states his reason for the merger. “Of the hundreds of companies we reviewed for our SPAC, 23andMe stands head and shoulders above the rest,” he said. “As an early investor, I have seen 23andMe develop into a company with enormous growth potential. Driven by [CEO Anne Wojcicki’s] vision to empower consumers, and with our support, I’m excited to see 23andMe make a positive difference to many more people’s lives.”
According to a 23andMe press release, the deal values the company at approximately $3.5 billion and will net the consumer genetics and research company as much as $759 million in additional cash. Wojcicki and Branson each invested $25 million themselves as part of the $250 million fund to take the company public.
“As a fellow industry disruptor as well as an early investor in 23andMe, we are thrilled to partner with Sir Richard Branson and VG Acquisition Corp. as we approach the next phase of our business, which will create new opportunities to revolutionize personalized healthcare and medicine,” 23andMe co-founder and CEO Anne Wojcicki (above) said in the press release. “We have always believed that healthcare needs to be driven by the consumer, and we have a huge opportunity to help personalize the entire experience at scale, allowing individuals to be more proactive about their health and wellness. Through a genetics-based approach, we fundamentally believe we can transform the continuum of healthcare.” (Photo copyright: Inc. magazine.)
Participation in Research Key to Future of DTC Genetics Testing
Though DTC genetic testing kit sales have slowed in recent years for both 23andMe and rival Ancestry, Wojcicki believes the company’s database of 10 million customers—with 80% of customers agreeing to participate in research—is the key to its future.
“We have always seen health as a much bigger opportunity” than genealogy, Wojcicki told The Wall Street Journal (WSJ).
According to the WSJ, 23andMe customers fill out more than 30,000 surveys each day on health and related issues. With that information, the company has determined its database includes 1.7 million people with high cholesterol, nearly 1.6 million with depression and 539,000 with Type 2 diabetes, information that is highly valued by medical researchers and those running clinical trials.
Personalizing Healthcare through DTC Genetic Testing
Wojcicki expects the merger will propel the consumer DNA-testing company into personalized medicine and therapeutics. “We have always believed that healthcare needs to be driven by the consumer, and we have a huge opportunity to help personalize the entire experience at scale, allowing individuals to be more proactive about their health and wellness,” Wojcicki said in a statement. “Through a genetics-based approach, we fundamentally believe we can transform the continuum of healthcare.”
In August 2020, the US Food and Drug Administration “granted 23andMe a 510(k) clearance for a pharmacogenetics report on two medications—Clopidogrel, prescribed for certain heart conditions, and Citalopram, which is prescribed for depression,” 23andMe announced in a blog post.
“This impactful pharmacogenetics information can now be delivered without the need for confirmatory testing, a testament to the clinical validity of 23andMe results,” said Kathy Hibbs, 23andMe Chief Legal and Regulatory Officer, in the blog post. “23andMe remains the only company with direct-to-consumer pharmacogenetic reports cleared by the FDA.”
23andMe’s trove of genetic data already has netted it a partnership with GlaxoSmithKline (GSK). According to a GSK press release, in 2018, the two companies signed a four-year research and development agreement. The collaboration targets novel medicines and potential cures using human genetics as the basis for discovery.
COVID-19 Boosts 23andMe’s Sales
During a joint interview with Branson in Bloomberg News about the merger, Wojcicki said, “COVID-19 has really opened up doors.” Now more than ever, she said, people are interested in preventative healthcare. “I’ve had this dream since 2003 that genetics would revolutionize healthcare and that’s really the era I see we can now usher in,” she added.
As 23andMe pushes further into personalized therapeutics, clinical laboratories and pathology groups would be wise to watch and see if this new entrant accelerates healthcare’s shift to the precision medicine model of personalized care.
Results of the UK study confirm for clinical laboratory professionals the importance of fully understanding the design and function of SNP chips they may be using in their labs
Here is another example of a long-established clinical laboratory test that—upon new evidence—turns out to be not as accurate as once thought. According to research conducted at the University of Exeter in Devon, UK, Single-nucleotide polymorphism (SNP) chips (aka, SNP microarrays)—technology commonly used in commercial genetic testing—is inadequate at detecting rare gene variants that can increase breast cancer risk.
A news release announcing the results of the large-scale study states, “A technology that is widely used by commercial genetic testing companies is ‘extremely unreliable’ in detecting very rare variants, meaning results suggesting individuals carry rare disease-causing genetic variants are usually wrong.”
Why is this a significant finding for clinical laboratories? Because medical laboratories performing genetic tests that use SNP chips should be aware that rare genetic variants—which are clinically relevant to a patient’s case—may not be detected and/or reported by the tests they are running.
UK Researchers Find ‘Shockingly High False Positives’
The conclusion reached by the Exeter researchers, the BMJ study states, is that “SNP chips are extremely unreliable for genotyping very rare pathogenic variants and should not be used to guide health decisions without validation.”
Leigh Jackson, PhD, Lecturer in Genomic Medicine at University of Exeter and co-author of the BMJ study, said in the news release, “The number of false positives on rare genetic variants produced by SNP chips was shockingly high. To be clear: a very rare, disease-causing variant detected using [an] SNP chip is more likely to be wrong than right.”
In the news release, Caroline Wright, PhD (above), Professor in Genomic Medicine at the University of Exeter Medical School and senior author of the BMJ study, said, “SNP chips are fantastic at detecting common genetic variants, yet we have to recognize that tests that perform well in one scenario are not necessarily applicable to others.” She added, “We’ve confirmed that SNP chips are extremely poor at detecting very rare disease-causing genetic variants, often giving false positive results that can have profound clinical impact. These false results had been used to schedule invasive medical procedures that were both unnecessary and unwarranted.” (Photo copyright: University of Exeter.)
Large-Scale Study Taps UK Biobank Data
The Exeter researchers were concerned about cases of unnecessary invasive medical procedures being scheduled by women after learning of rare genetic variations in BRCA1 (breast cancer type 1) and BRCA2 (breast cancer 2) tests.
“The inherent technical limitation of SNP chips for correctly detecting rare genetic variants is further exacerbated when the variants themselves are linked to very rare diseases. As with any diagnostic test, the positive predictive value for low prevalence conditions will necessarily be low in most individuals. For pathogenic BRCA variants in the UK Biobank, the SNP chips had an extremely low positive predictive value (1-17%) when compared with sequencing. Were these results to be fed back to individuals, the clinical implications would be profound. Women with a positive BRCA result face a lifetime of additional screening and potentially prophylactic surgery that is unwarranted in the case of a false positive result,” they wrote.
Using UK Biobank data from 49,908 participants (55% were female), the researchers compared next-generation sequencing (NGS) to SNP chip genotyping. They found that SNP chips—which test genetic variation at hundreds-of-thousands of specific locations across the genome—performed well when compared to NGS for common variants, such as those related to type 2 diabetes and ancestry assessment, the study noted.
“Because SNP chips are such a widely used and high-performing assay for common genetic variants, we were also surprised that the differing performance of SNP chips for detecting rare variants was not well appreciated in the wider research or medical communities. Luckily, we had recently received both SNP chip and genome-wide DNA sequencing data on 50,000 individuals through the UK Biobank—a population cohort of adult volunteers from across the UK. This large dataset allowed us to systematically investigate the performance of SNP chips across millions of genetic variants with a wide range of frequencies, down to those present in fewer than 1 in 50,000 individuals,” wrote Wright and Associate Professor of Bioinformatics and Human Genetics at Exeter, Michael Weedon, PhD, in a BMJ blog post.
The Exeter researchers also analyzed data from a small group of people in the Personal Genome Project who had both SNP genotyping and sequencing information available. They focused their analysis on rare pathogenic variants in BRCA1 and BRCA2 genes.
The researchers found:
The rarer the variant, the less reliable the test result. For example, for “very rare variants” in less than one in 100,000 people, 84% found by SNP chips were false positives.
Low positive predictive values of about 16% for very rare variants in the UK Biobank.
Nearly all (20 of 21) customers of commercial genetic testing had at least one false positive rare disease-causing variant incorrectly genotyped.
SNP chips detect common genetic variants “extremely well.”
Advantages and Capabilities of SNP Chips
Compared to next-gen genetic sequencing, SNP chips are less costly. The chips use “grids of hundreds of thousands of beads that react to specific gene variants by glowing in different colors,” New Scientist explained.
Common variants of BRCA1 and BRCA2 can be found using SNP chips with 99% accuracy, New Scientist reported based on study data.
However, when the task is to find thousands of rare variants in BRCA1 and BRCA2 genes, SNP chips do not fare so well.
“It is just not the right technology for the job when it comes to rare variants. They’re excellent for the common variants that are present in lots of people. But the rarer the variant is, the less likely they are to be able to correctly detect it,” Wright told CNN.
SNP chips can’t detect all variants because they struggle to cluster needed data, the Exeter researchers explained.
“SNP chips perform poorly for genotyping rare genetic variants owing to their reliance on data clustering. Clustering data from multiple individuals with similar genotypes works very well when variants are common,” the researchers wrote. “Clustering becomes more difficult as the number of people with a particular genotype decreases.”
Clinical laboratories Using SNP Chips
The researchers at Exeter unveiled important information that pathologists and medical laboratory professionals will want to understand and monitor. Cancer patients with rare genetic variants may not be diagnosed accurately because SNP chips were not designed to identify specific genetic variants. Those patients may need additional testing to validate diagnoses and prevent harm.
