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Clinical Trial Shows New Laboratory Developed Blood Test 83% Effective at Detecting Colorectal Cancer

Accurate blood-based clinical laboratory testing for cancer promises to encourage more people to undergo early screening for deadly diseases

One holy grail in diagnostics is to develop less-invasive specimen types when screening or testing for different cancers. This is the motivation behind the creation of a new assay for colorectal (colon) cancer that uses a blood sample and that could be offered by clinical laboratories. The data on this assay and its performance was featured in a recent issue of the New England Journal of Medicine(NEJM).

The company developing this new test recognized that more than 50,000 people will die in 2024 from colon cancer, according to the American Cancer Society. That’s primarily because people do not like colonoscopies even though the procedure can detect cancer in its early stages. Similarly, patients tend to find collecting their own fecal samples for colon cancer screening tests to be unpleasant.

But the clinical laboratory blood test for cancer screening developed by Guardant Health may make diagnosing the deadly disease less invasive and save lives. The test “detects 83% of people with colorectal cancer with specificity of 90%,” a company press release noted.

“Early detection could prevent more than 90% of colorectal cancer-related deaths, yet more than one third of the screening-eligible population is not up to date with screening despite multiple available tests. A blood-based test has the potential to improve screening adherence, detect colorectal cancer earlier, and reduce colorectal cancer-related mortality,” the study authors wrote in the NEJM.

As noted above, this is the latest example of test developers working to develop clinical laboratory tests that are less invasive for patients, while equaling or exceeding the sensitivity and specificity of existing diagnostic assays for certain health conditions.

“I do think having a blood draw versus undergoing an invasive test will reach more people, My hope is that with more tools we can reach more people,” Barbara H. Jung, MD (above), President of the American Gastroenterological Association, told NPR. Clinical laboratory blood tests for cancer may encourage people who do not like colonoscopies to get regular screening. (Photo copyright: American Gastroenterology Association.)

Developing the Shield Blood Test

Colorectal cancer is the “third most common cancer among men and women in the US,” according to the American Gastrological Association (AGA). And yet, millions of people do not get regular screening for the disease.

To prove their Shield blood test, Guardant Health, a precision oncology company based in Redwood City, Calif., enrolled more than 20,000 patients between the ages of 45-84 from across the US in a prospective, multi-site registrational study called ECLIPSE (Evaluation of ctDNA LUNAR Assay In an Average Patient Screening Episode).

“We assessed the performance characteristics of a cell-free DNA (cfDNA) blood-based test in a population eligible for colorectal cancer screening. The coprimary outcomes were sensitivity for colorectal cancer and specificity for advanced neoplasia (colorectal cancer or advanced precancerous lesions) relative to screening colonoscopy. The secondary outcome was sensitivity to detect advanced precancerous lesions,” the study authors wrote in the NEJM.

In March, Guardant completed clinical trials of its Shield blood test for detecting colorectal cancer (CRC) in men and women. According to the company press release, the test demonstrated:

  • 83% sensitivity in detecting individuals with CRC.
  • 88% sensitivity in detecting pathology-confirmed Stages I-III.

Additionally, the Shield test showed sensitivity by stage of:

  • 65% for pathology-confirmed Stage I,
  • 55% for clinical Stage I,
  • 100% for Stage II, and
  • 100% for Stage III.

“The results of the study are a promising step toward developing more convenient tools to detect colorectal cancer early while it is more easily treated,” said molecular biologist and gastroenterologist William M. Grady, MD, Medical Director, Gastrointestinal Cancer Prevention Program at Fred Hutchinson Cancer Center and corresponding author of the ECLIPSE study in the press release. “The test, which has an accuracy rate for colon cancer detection similar to stool tests used for early detection of cancer, could offer an alternative for patients who may otherwise decline current screening options.”

Are Colonoscopies Still Needed?

“More than three out of four Americans who die from colorectal cancer are not up to date with their recommended screening, highlighting the need for a more convenient and less invasive screening method that can overcome barriers associated with traditional options,” Daniel Chung, MD, gastroenterologist at Massachusetts General Hospital and Professor of Medicine at Harvard Medical School, said in the Guardant press release.

Barbara H. Jung, MD, President of the American Gastroenterological Association, says that even if Guardant’s Shield test makes it to the public the “dreaded colonoscopy” will still be needed because the procedure is used to locate and test polyps. “And when you find those you can also remove them, which in turn prevents the cancer from forming,” she told NPR.

There is hope that less invasive clinical laboratory testing will encourage more individuals to get screened for cancer earlier and regularly, and that the shift will result in a reduction in cancer rates.

“Colorectal cancer is highly treatable if caught in the early stages,” said Chris Evans, President of the Colon Cancer Coalition, in the Guardant press release.

Guardant Health’s ECLIPSE study is a prime example of the push clinical laboratory test developers are making to create user-friendly test options that make it easier for patients to follow through with regular screening for early detection of diseases. It echoes a larger effort in the medical community to think outside the box and come up with creative solutions to reach wider audiences in the name of prevention.

—Kristin Althea O’Connor

Related Information:

Guardant Health ECLIPSE Study Data Demonstrating Efficacy of Shield Blood-based Test for Colorectal Cancer Screening to be Published in The New England Journal of Medicine

A Cell-free DNA Blood-Based Test for Colorectal Cancer Screening

Guardant Health Announces Positive Results from Pivotal ECLIPSE Study Evaluating a Blood Test for the Detection of Colorectal Cancer

A Simple Blood Test Can Detect Colorectal Cancer Early, Study Finds

Key Statistics for Colorectal Cancer

Colorectal Cancer Facts and Statistics

Cancer Stat Facts: Colorectal Cancer

Penn Medicine Study Shows Telemedicine Can Cut Employer Healthcare Costs by 25%

This is good news for clinical laboratories that already perform medical testing for telehealth providers and an opportunity for medical labs that do not, it is an opportunity to do so

Telemedicine visits have become commonplace since the arrival of COVID-19. Before the pandemic, telehealth was primarily used to give remote patients access to quality healthcare providers. But three years later both patients and physicians are becoming increasingly comfortable with virtual office visits, especially among Millennial and Gen Z patients and doctors.

Now, a recent study by the Perelman School of Medicine at the University of Pennsylvania (Penn Medicine) suggests that there could be a significant financial advantage for hospitals that conduct telemedicine. This would be a boon to clinical laboratories that perform medical testing for telemedicine providers.

According to Digital Health News, in July 2017 Penn Medicine launched a 24/7/365 copayment-free telemedicine program for its employees called Penn Medicine OnDemand. To engage with a telemedicine provider, patients must have a smartphone or tablet with a front-facing camera and updated operating system.

Telemedicine Visits Cost Less than In-Office Doctor Appointments

An analysis of the OnDemand program’s data collected from its inception through the end of 2019 found that the telemedicine appointment per-visit cost averaged around $380, whereas the cost of an in-person visit at an emergency department, primary care office, or urgent care clinic averaged around $493.

Typically, Penn Medicine’s employees used the telemedicine program for common, low risk health complaints. Healthcare conditions that many patients might otherwise not seek treatment for if an in-office visit was inconvenient.

“The data we analyzed pre-date the pandemic. It was a time when people were just putting a toe in the water and wondering, ‘Let me see if telemedicine could treat my needs,’” Krisda Chaiyachati MD, an internal medicine physician and Adjunct Assistant Professor at Penn Medicine, told Digital Health News. Chaiyachati lead the research team that conducted the telemedicine study.

“These days, people seem willing to jump in for an appropriate set of conditions,” he added. “The good news is that we made care easier while saving money, and we think the savings could be higher in the future.”

Chaiyachati and his colleagues found that telemedicine can save employers healthcare costs without sacrificing quality of care.

The Penn Medicine researchers published their findings in The American Journal of Managed Care, titled, “Economics of a Health System’s Direct-to-Consumer Telemedicine for Its Employees.”

Krisda Chaiyachati MD

“The conditions most often handled by OnDemand are low acuity—non-urgent or semi-urgent issues like respiratory infections, sinus infections, and allergies—but incredibly common, so any kind of cost reduction can make a huge difference for controlling employee benefit costs,” Krisda Chaiyachati MD (above), a Penn Medicine physician and the study’s lead researcher, told Digital Health News. Clinical laboratories that already perform testing for telemedicine providers may see an increase in test orders once hospitals learn of the costs savings highlighted in the Penn Medicine study. (Photo copyright: Penn Medicine.)

Telemedicine on the Rise

The idea is not new. In late 2018, Planned Parenthood launched the Planned Parenthood Direct mobile app in New York State. The app provides New York patients with access to birth control, emergency contraception, and UTI treatment with no in-person visit required.

The program has since expanded across the country. Users of the app can connect with a physician to go over symptoms/needs, and the be sent a prescription within a business day to the pharmacy of their choice.

The concept is similar to Penn Medicine OnDemand, which gives patients 24/7 year around access to treatment for common and low-acuity medical issues in a convenient, virtual process.  

Telemedicine was on the rise in other parts of the healthcare industry before the pandemic. According to “The State of Telehealth Before and After the COVID-19 Pandemic” published by Julia Shaver, MD, Kaiser Permanente, in the journal Primary Care: Clinics in Office Practice, 76% of US hospital systems had utilized some form of telemedicine by 2018. This rate grew exponentially while the healthcare system had to navigate a world with COVID-19 on the rise.

And, apparently, quality of care does not suffer when moved from in-person to virtual settings. Two studies conducted by The University of Rochester Medical Center (URMC) found telemedicine to be effective and that “common concerns about telemedicine don’t hold up to scrutiny,” according a news release.

In her New England Journal of Medicine (NEJM) paper on the studies, Kathleen Fear, PhD, URMC’s Director of Data Analytics, Health Lab, and her co-authors, wrote: “Three beliefs—that telemedicine will reduce access for the most vulnerable patients; that reimbursement parity will encourage overuse of telemedicine; and that telemedicine is an ineffective way to care for patients—have for years formed the backbone of opposition to the widespread adoption of telemedicine.”

However, URMC’s study found the opposite to be true. The NEJM authors wrote, “there is no support for these three common notions about telemedicine. At URMC, the most vulnerable patients had the highest uptake of telemedicine; not only did they complete a disproportionate share of telemedicine visits, but they also did so with lower no-show and cancellation rates. It is clear that … telemedicine makes medical care more accessible to patients who previously have experienced substantial barriers to care.

“Importantly, this access does not come at the expense of effectiveness. Providers do not order excessive amounts of additional testing to make up for the limitations of virtual visits. Patients do not end up in the ER or the hospital because their needs are not met during a telemedicine visit, and they also do not end up requiring additional in-person follow-up visits to supplement their telemedicine visit,” the NEJM authors concluded.

“Not only did our most vulnerable patients not get left behind—they were among those engaging the most with, and benefiting the most from, telemedicine services. We did not see worse outcomes or increased costs, or patients needing an increased amount of in-person follow up. Nor did we find evidence of overuse. This is good care, and it is equitable care for vulnerable populations,” Fear said in the news release.

“For patients, the message is clear and reassuring: Telemedicine is an effective and efficient way of receiving many kinds of healthcare,” she added.

Opportunities for Clinical Laboratories

Dark Daily has covered the fast growing world of telemedicine in many ebriefs over the years.

In “Two New Definitive Healthcare Surveys Show Use of Inpatient Telehealth is Outpacing Outpatient Telehealth Services,” we covered how medical laboratories could help hospital telehealth physicians in ordering clinical laboratory tests and reviewing test results to ensure selecting the best therapies.

And in “Despite Technical Challenges During COVID-19 Pandemic, Healthcare Networks Plan to Increase Investment in Telehealth Technologies,” we reported on a survey which showed that in 2021 more than 50% of hospitals and health systems planned to increase virtual care services within two years, a development that we predicted could change how patients access clinical laboratory testing services. And it has.

As telemedicine broadens its reach across the healthcare world, clinical laboratories and pathology groups would be wise to seek collaboration with health plans and providers of telemedicine to figure out where sample collection and testing fits into this new virtual healthcare space.

Ashley Croce

Related Information:

Telemedicine Visits Cut Health System Employee Care Costs by Nearly 25%

Planned Parenthood’s Mobile App Brings Birth Control Pills and UTI Treatment to New Yorkers’ Doorsteps

The State of Telehealth Before and After the COVID-19 Pandemic

Myths Busted: New Studies Show Telemedicine is Effective, Doesn’t Reduce Access to Care

Two New Definitive Healthcare Surveys Show Use of Inpatient Telehealth is Outpacing Outpatient Telehealth Services

Despite Technical Challenges During COVID-19 Pandemic, Healthcare Networks Plan to Increase Investment in Telehealth Technologies

England’s National Health Service to Offer Widespread Rapid Whole Genome Sequencing for Children and Babies

Research in the UK and US into how rapid WGS can prevent deaths and improve outcomes for kids with rare genetic diseases may lead to more genetic testing based in local clinical laboratories

Genetic scientists with the National Health Service (NHS) in England have embarked on an ambitious plan to offer rapid whole genome sequencing (rWGS) for children and babies with serious illnesses, as part of a larger initiative to embrace genomic medicine in the United Kingdom (UK).

The NHS estimates that the plan will benefit more than 1,000 children and babies each year, including newborns with rare diseases such as cancer, as well as kids placed in intensive care after being admitted to hospitals. Instead of waiting weeks for results from conventional tests, clinicians will be able to administer a simple blood test and get results within days, the NHS said in a press release.

The press release notes that about 75% of rare genetic diseases appear during childhood “and are responsible for almost a third of neonatal intensive care deaths.”

Here in the United States, pathologists and clinical laboratory managers should see this development as a progressive step toward expanding access to genetic tests and whole genome sequencing services. The UK is looking at this service as a nationwide service. By contrast, given the size of the population and geography of the United States, as this line of medical laboratory testing expands in the US, it will probably be centered in select regional centers of excellence.

The NHS laid out its implementation plan in a strategy paper published on NHS England’s website titled, “Accelerating Genomic Medicine in the NHS.”

“This strategy sets out how more people will be empowered to take preventative action following risk-based predictions, receive life-changing diagnoses, and get the support needed to live with genomically-informed diagnoses alongside improved access to cutting-edge precision [medicine] treatments. It also outlines how the NHS will accelerate future high-quality genomic innovation that can be adopted and spread across the country, leading to positive impacts for current and future generations,” the NHS wrote.

Amanda Pritchard

“This global first is an incredible moment for the NHS and will be revolutionary in helping us to rapidly diagnose the illnesses of thousands of seriously ill children and babies—saving countless lives in the years to come,” said NHS chief executive Amanda Pritchard (above) in a press release announcing the program. (Photo copyright: Hospital Times.)

New Rapid Whole Genome Sequencing Service

The NHS announced the plan following a series of trials last year. In one trial, a five-day old infant was admitted to a hospital in Cheltenham, Gloucester, with potentially deadly levels of ammonia in his blood. Whole genome sequencing revealed that changes in the CPS1 gene were preventing his body from breaking down nitrogen, which led to the spike in ammonia. He was given life-saving medication in advance of a liver transplant that doctors believed would cure the condition. Without the rapid genetic test, doctors likely would have performed an invasive liver biopsy.

Following sample collection at NHS locations, the genetic tests will be performed at the new National Rapid Whole Genome Sequencing Service, part of the South West NHS Genomic Laboratory Hub run by the Royal Devon University Healthcare NHS Foundation Trust in Exeter, UK.

Using a simple blood test, the new newborn genetic screening service in England is expected to benefit more than 1,000 critically ill infants each year, potentially saving their lives. “The rapid whole genome testing service will transform how rare genetic conditions are diagnosed,” explained Emma Baple, PhD, Professor of Genomic Medicine at University of Exeter Medical School and leader of the National Rapid Whole Genome Sequencing Service in the press release. “We know that with prompt and accurate diagnosis, conditions could be cured or better managed with the right clinical care, which would be life-altering—and potentially life-saving—for so many seriously unwell babies and children,” Precision Medicine Institute reported.

According to The Guardian, test results will be available in two to seven days.

Along with the new rWGS testing service, the NHS announced a five-year plan to implement genomic medicine more broadly. The provisions include establishment of an ethics advisory board, more training for NHS personnel, and an expansion of genomic testing within the existing NHS diagnostic infrastructure. The latter could include using NHS Community Diagnostics centers to collect blood samples from family members to test for inherited diseases.

UK’s Longtime Interest in Whole Genome Sequencing

The UK government has long been interested in the potential role of WGS for delivering better outcomes for patients with genetic diseases, The Guardian reported.

In 2013, the government launched the 100,000 Genomes Project to examine the usefulness of the technology. In November 2021, investigators with the project reported the results of a large pilot study in which they analyzed the genomes of 4,660 individuals with rare diseases. The study, published in the New England Journal of Medicine (NEJM) titled, “100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care—Preliminary Report,” found “a substantial increase in yield of genomic diagnoses made in patients with the use of genome sequencing across a broad spectrum of rare disease.”

The study’s findings suggest that use of WGS “could save the NHS millions of pounds,” The Guardian reported.

Whole Genome Sequencing System for Newborns in the US

Researchers in the United States are also looking at the potential for WGS to improve health outcomes in children with genetic conditions. Last August, a research team led by Stephen F. Kingsmore, MD, DSc, President/CEO of Rady Children’s Institute for Genomic Medicine in San Diego, authored a study published in the American Journal of Human Genetics (AJHG) titled, “A Genome Sequencing System for Universal Newborn Screening, Diagnosis, and Precision Medicine for Severe Genetic Diseases,” that described a scalable prototype for a newborn screening system.

“This NBS-rWGS [newborn screening by rapid whole genome sequencing] system is designed to complement the existing newborn screening process and has the potential to eliminate the diagnostic and therapeutic odyssey that many children and parents face,” Kingsmore said in a press release. “Currently, only 35 core genetic disorders are recommended for newborn screening in the United States, but there are more than 7,200 known genetic diseases. Outcomes remain poor for newborns with a genetic disease because of the limited number of recommended screenings. With NBS-rWGS, we can more quickly expand that number and therefore potentially improve outcomes through precision medicine.”

A more recent 2023 study which examined 112 infant deaths at Rady Children’s Hospital found that 40% of the babies had genetic diseases. In seven infants, genetic diseases were identified post-mortem, and in five of them “death might have been avoided had rapid, diagnostic WGS been performed at time of symptom onset or regional intensive care unit admission,” the authors wrote.

“Prior etiologic studies of infant mortality are generally retrospective, based on electronic health record and death certificate review, and without genome information, leading to underdiagnosis of genetic diseases,” said Christina Chambers, PhD, co-author of the study, in a press release. “In fact, prior studies show at least 30% of death certificates have inaccuracies. By implementing broad use of genome sequencing in newborns we might substantially reduce infant mortality.” 

Pioneering work with whole genome sequencing for newborns, such as that being conducted by the clinical laboratory and genetic teams at Rady Children’s Hospital and the UK’s NHS, could allow doctors to make timely interventions for our most vulnerable patients.

—Stephen Beale

Related Information:

Study Suggests DNA Sequencing Could Reduce Infant Deaths, Often Caused by Genetic Disease

Novel Newborn Screening System Uses Rapid Whole Genome Sequencing and Acute Management Guidance to Screen and Diagnosis Genetic Diseases

Study Finds Association of Genetic Disease and Infant Mortality Higher than Previously Recognized: 41% of Infant Deaths Associated with Genetic Diseases

Genome Sequencing Could Prevent Infant Deaths

A Genome Sequencing System for Universal Newborn Screening, Diagnosis, and Precision Medicine for Severe Genetic Diseases

Genetic Testing in the PICU Prompts Meaningful Changes in Care

Major Policy Event in United Kingdom Aligns National Genetic Screening Program Using Rapid Whole Genome Sequencing

World-First National Genetic Testing Service to Deliver Rapid Life-Saving Checks for Babies and Kids

Genome Sequencing Trial to Test Benefits of Identifying Genetic Diseases at Birth

New NHS Genetic Testing Service ‘Could Save Thousands of Children’ in England

NHS England Completes Move Towards Rapid Whole Genome Sequencing of All Critically Ill Infants

Whole Genome Sequencing for Children: An Information Guide for Parents, Carers, and Families

Another Milestone for CRISPR-Cas9 Technology: First Trial Data for Treatment Delivered Intravenously

Unlike most other CRISPR/Cas-9 therapies that are ex vivo treatments in which cells are modified outside the body, this study was successful with an in vivo treatment

Use of CRISPR-Cas9 gene editing technology for therapeutic purposes can be a boon for clinical laboratories. Not only is this application a step forward in the march toward precision medicine, but it can give clinical labs the essential role of sequencing a patient’s DNA to help the referring physician identify how CRISPR-Cas9 can be used to edit the patient’s DNA to treat specific health conditions.

Most pathologists and medical lab managers know that CRISPR-Cas9 gene editing technology has been touted as one of the most significant advances in the development of therapies for inherited genetic diseases and other conditions. Now, a pair of biotech companies have announced a milestone for CRISPR-Cas9 with early clinical data involving a treatment delivered intravenously (in vivo).

The therapy, NTLA-2001, was developed by Intellia Therapeutics (NASDAQ:NTLA) and Regeneron Pharmaceuticals (NASDAQ:REGN) for treatment of hereditary ATTR (transthyretin) amyloidosis, a rare and sometimes fatal liver disease.  

As with other therapies, determining which patients are suitable candidates for specific treatments is key to the therapy’s success. Therefore, clinical laboratories will play a critical role in identifying those patients who would most likely benefit from a CRISPR-delivered therapy.

Such is the goal of precision medicine. As methods are refined that can correct unwelcome genetic mutations in a patient, the need to do genetic testing to identify and diagnose whether a patient has a specific gene mutation associated with a specific disease will increase.

The researchers published data from a Phase 1 clinical trial of NTLA-2001 in the New England Journal of Medicine (NEJM), titled, “CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis.” They also presented their findings at the Peripheral Nerve Society (PNS) Annual Meeting.

What is NTLA-2001 and Why Is It Important?

Cleveland Clinic describes ATTR amyloidosis as a “protein misfolding disorder” involving transthyretin (TTR), a protein made in the liver. The disease leads to deposits of the protein in the heart, nerves, or other organs.

According to Intellia and Regeneron, NTLA-2001 is designed to inactivate the gene that produces the protein.

The interim clinical trial data indicated that one 0.3 mg per kilogram dose of the therapy reduced serum TTR by an average of 87% at day 28. A smaller dose of 0.1 mg per kilogram reduced TTR by an average of 52%. The researchers reported “few adverse events” in the six study patients, “and those that did occur were mild in grade.”

Current treatments, the companies stated, must be administered regularly and typically reduce TTR by about 80%.

“These are the first ever clinical data suggesting that we can precisely edit target cells within the body to treat genetic disease with a single intravenous infusion of CRISPR,” said Intellia President and CEO John Leonard, MD, in a press release. “The interim results support our belief that NTLA-2001 has the potential to halt and reverse the devastating complications of ATTR amyloidosis with a single dose.”

He added that “solving the challenge of targeted delivery of CRISPR-Cas9 to the liver, as we have with NTLA-2001, also unlocks the door to treating a wide array of other genetic diseases with our modular platform, and we intend to move quickly to advance and expand our pipeline.”

Daniel Anderson, PhD

“It’s an important moment for the field,” MIT biomedical engineer Daniel Anderson, PhD (above), told Nature. Anderson is Professor, Chemical Engineering and Institute for Medical Engineering and Science at the Koch Institute for Integrative Cancer Research at MIT. “It’s a whole new era of medicine,” he added. Advances in the use of CRISPR-Cas9 for therapeutic purposes will create the need for clinical laboratories to sequence patients’ DNA to help physicians determine the best uses for a CRISPR-Cas9 treatment protocol. (Photo copyright: Massachusetts Institute of Technology.)

In Part 2 of the Phase 1 trial, Intellia plans to evaluate the new therapy at higher doses. After the trial is complete, “the company plans to move to pivotal studies for both polyneuropathy and cardiomyopathy manifestations of ATTR amyloidosis,” the press release states.

Previous clinical trials reported results for ex vivo treatments in which cells were removed from the body, modified with CRISPR-Cas9 techniques, and then reinfused. “But to be able to edit genes directly in the body would open the door to treating a wider range of diseases,” Nature reported.

How CRISPR-Cas9 Works

On its website, CRISPR Therapeutics, a company co-founded by Emmanuelle Charpentier, PhD, a director at the Max Planck Institute for Infection Biology in Berlin, and inventor of CRISPR-Cas9 gene editing, explained that the technology “edits genes by precisely cutting DNA and then letting natural DNA repair processes take over.” It can remove fragments of DNA responsible for causing diseases, as well as repairing damaged genes or inserting new ones.

The therapies have two components: Cas9, an enzyme that cuts the DNA, and Guide RNA (gRNA), which specifies where the DNA should be cut.

Charpentier and biochemist Jennifer Doudna, PhD, Nobel Laureate, Professor of Chemistry, Professor of Biochemistry and Molecular Biology, and Li Ka Shing Chancellor’s Professor in Biomedical and Health at the University of California Berkeley, received the 2020 Nobel Prize in Chemistry for their work on CRISPR-Cas9, STAT reported.

It is important to pathologists and medical laboratory managers to understand that multiple technologies are being advanced and improved at a remarkable pace. That includes the technologies of next-generation sequencing, use of gene-editing tools like CRISPR-Cas9, and advances in artificial intelligence, machine learning, and neural networks.

At some future point, it can be expected that these technologies will be combined and integrated in a way that allows clinical laboratories to make very early and accurate diagnoses of many health conditions.

—Stephen Beale

Related Information

Intellia and Regeneron Announce Landmark Clinical Data Showing Deep Reduction in Disease-Causing Protein After Single Infusion of NTLA-2001, an Investigational CRISPR Therapy for Transthyretin (ATTR) Amyloidosis

CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis

Landmark CRISPR Trial Shows Promise Against Deadly Disease

CRISPR Milestone Pushes Gene Editing Toward Its Promise

CRISPR Clinical Trials: A 2021 Update

CRISPR Gene Therapy: Applications, Limitations, and Implications for the Future

Diseases CRISPR Could Cure: Latest Updates on Research Studies and Human Trials

Faster, Better, Cheaper: The Rise of CRISPR in Disease Detection

The Potential of CRISPR-Based Diagnostic Assays and Treatment Approaches Against COVID-19

Two Female CRISPR Scientists Make History, Winning Nobel Prize in Chemistry for Genome-Editing Discovery

Multiple Studies Raise Questions About Reliability of Clinical Laboratory COVID-19 Diagnostic Tests

In the absence of a “gold standard,” researchers are finding a high frequency of false negatives among SARS-CoV-2 RT-PCR tests

Serology tests designed to detect antibodies to the SARS-CoV-2 coronavirus that causes the COVID-19 illness have been dogged by well-publicized questions about accuracy. However, researchers also are raising concerns about the accuracy of molecular diagnostics which claim to detect the actual presence of the coronavirus itself.

“Diagnostic tests, typically involving a nasopharyngeal swab, can be inaccurate in two ways,” said Steven Woloshin, MD, MS, in a news release announcing a new report that “examines challenges and implications of false-negative COVID-19 tests.” Woloshin is an internist, a professor at Dartmouth Institute, and co-director of the Geisel School of Medicine at Dartmouth.

“A false-positive result mistakenly labels a person infected, with consequences including unnecessary quarantine and contact tracing,” he stated in the news release. “False-negative results are far more consequential, because infected persons who might be asymptomatic may not be isolated and can infect others.”

Woloshin led a team of Dartmouth researchers who analyzed two studies from Wuhan, China, and a literature review by researchers in Europe and South America that indicated diagnostic tests for COVID-19 are frequently generating false negatives. The team published their results in the June 5 New England Journal of Medicine (NEJM).

For example, one research team in Wuhan collected samples from 213 hospitalized COVID-19 patients and found that an approved RT-PCR test produced false negatives in 11% of sputum samples, 27% of nasal samples, and 40% of throat samples. Their research was published on the medRxiv preprint server and has not been peer-reviewed.

The literature review Woloshin’s team studied was also published on medRxiv, titled, “False-Negative Results of Initial Rt-PCR Assays for COVID-19: A Systematic Review.” It indicated that the rate of false negatives could be as high as 29%. The authors of the review looked at five studies that had enrolled a total of 957 patients. “The collected evidence has several limitations, including risk of bias issues, high heterogeneity, and concerns about its applicability,” they wrote. “Nonetheless, our findings reinforce the need for repeated testing in patients with suspicion of SARS-Cov-2 infection.”

Another literature review, published in the Annals of Internal Medicine, titled, “Variation in False-Negative Rate of Reverse Transcriptase Polymerase Chain Reaction–Based SARS-CoV-2 Tests by Time Since Exposure,” estimated the probability of false negatives in RT-PCR tests at varying intervals from the time of exposure and symptom onset. For example, the authors found that the median false-negative rate was 38% if a test was performed on the day of symptom onset, versus 20% three days after onset. Their analysis was based on seven studies, five of which were peer-reviewed, with a total of 1330 test samples.

Doctors also are seeing anecdotal evidence of false negatives. For example, clinicians at UC San Diego Health medical center treated a patient with obvious symptoms of COVID-19, but two tests performed on throat samples were negative. However, a third test, using a sample from a bronchial wash, identified the virus, reported Medscape.

The lesson for clinicians is that they can’t rely solely on test results but must also consider their own observations of the patient, Joshua Metlay, MD, PhD, of Massachusetts General Hospital told Medscape.

Sensitivity and Specificity of COVID-19 Clinical Laboratory Tests

The key measures of test accuracy are sensitivity, which refers to the ability to detect the presence of the virus, and specificity, the ability to determine that the targeted pathogen is not present. “So, a sensitive test is less likely to provide a false-negative result and a specific test is less likely to provide a false-positive result,” wrote Kirsten Meek, PhD, medical writer and editor, in an article for ARUP Laboratories.

“Analytic” sensitivity and specificity “represent the accuracy of a test under ideal conditions in which specimens have been collected from patients with either high viral loads or a complete absence of exposure,” she wrote. However, “sensitivity and specificity under real-world conditions, in which patients are more variable and specimen collection may not be ideal, can often be lower than reported numbers.”

In a statement defending its ID Now molecular point-of-care test, which came under scrutiny during a study of COVID-19 molecular tests by NYU Langone Health, Northwell Health, and Cleveland Clinic, according to MedTech Dive, Abbott Laboratories blamed improper sample collection and handling for highly-publicized false negatives produced by its rapid test. An FDA issued alert about the test on May 14 noted that Abbott had agreed to conduct post-market studies to identify the cause of the false negatives and suggest remedial actions.

Issues with Emergency Use Authorizations

In their NEJM analysis, Woloshin et al point to issues with the FDA’s process for issuing Emergency Use Authorizations (EUAs). For example, they noted variations in how manufacturers are conducting clinical evaluations to determine test performance. “The FDA prefers the use of ‘natural clinical specimens’ but has permitted the use of ‘contrived specimens’ produced by adding viral RNA or inactivated virus to leftover clinical material,” they wrote.

When evaluating clinical performance, manufacturers ordinarily conduct an index test of patients and compare the results with reference-standard test, according to the Dartmouth researchers. For people showing symptoms, the reference standard should be a clinical diagnosis performed by an independent adjudication panel. However, they wrote, “it is unclear whether the sensitivity of any FDA-authorized commercial test has been assessed in this way.” Additionally, a reference standard for determining sensitivity in asymptomatic people “is an unsolved problem that needs urgent attention to increase confidence in test results for contact-tracing or screening purposes.”

Stephen Rawlings, MD, PhD
“To truly determine false negatives, you need a gold standard test, which is essentially as close to perfect as we can get,” Stephen Rawlings, MD, PhD, (above), a resident physician of internal medicine and infectious diseases fellow at UC San Diego’s Center for AIDS Research (CFAR), who has been working on SARS-CoV-2 test validation since March. “But there just isn’t one yet for coronavirus,” he told Medscape. (Photo copyright: University of California, San Diego.)

In a perspective for Mayo Clinic Proceedings, Colin P. West, MD, PhD; Victor M. Montori, MD, MSc; and Priya Sampathkumar, MD, offered four recommendations for addressing concerns about testing accuracy:

  • Continued adherence to current measures, such as physical distancing and surface disinfection.
  • Development of highly sensitive and specific tests or combinations of tests to minimize the risk of false-negative results and ongoing transmission based on a false sense of security.
  • Improved RT-PCR tests and serological assays.
  • Development and communication of clear risk-stratified protocols for management of negative COVID-19 test results.

“These protocols must evolve as diagnostic test, transmission, and outcome statistics become more available,” they wrote.

Meanwhile, clinical laboratories remain somewhat on their own at selecting which COVID-19 molecular and serology tests they want to purchase and run in their labs. Complicating such decisions is the fact that many of the nation’s most reputable in vitro diagnostics manufacturers cannot produce enough of their COVID-19 tests to meet demand.

Consequently, when looking to purchase tests for SARS-CoV-2, smaller medical laboratory organizations find themselves evaluating COVID-19 kits developed by little-known or even brand-new companies.

—Stephen Beale

Related Information:

New Report Examines Challenges and Implications of False-Negative COVID-19 Tests

Questions about COVID-19 Test Accuracy Raised Across the Testing Spectrum

COVID-19 Test Results: Don’t Discount Clinical Intuition

FDA Provides New Tool to Aid Development and Evaluation of Diagnostic Tests That Detect SARS-CoV-2 Infection

EUA Authorized Serology Test Performance

Emergency Use Authorization (EUA) Information and List of All Current EUAs 

Coronavirus (COVID-19) Update: FDA Provides Promised Transparency for Antibody Tests

Understanding Medical Tests: Sensitivity, Specificity, and Positive Predictive Value

Webinar Part 1: Quality Issues Your Clinical Laboratory Should Know Before You Buy or Select COVID-19 Serology Tests

Webinar Part 2: Achieving High Confidence Levels in the Quality and Accuracy of Your Clinical Lab’s Chosen COVID-19 Serology Tests, featuring James Westgard, PhD

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