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 Their research was published on the medRxiv preprint server and has not been peer-reviewed.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.
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.”
“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.)
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.
Lab leaders may recall similar requests for data from other government agencies and wonder if FTC will take steps to investigate pricing and competition among clinical laboratories as well
It appears that the Federal Trade Commission (FTC) is ready to look into hospital consolidation, as evidenced by the extent of data—including pricing and managed care contracts—it requested from healthcare providers and health insurers last fall. This may not seem unusual to clinical laboratory leaders who remember having to respond to similar requests for information back in 2011.
In October of 2019, the federal agency took the unusual action of ordering two healthcare provider systems in Tennessee and West Virginia, as well as five health insurers, to share vast amounts of data “to study the effects of Certificates of Public Advantage (COPAs) on prices, quality, access, and innovation of healthcare services. The FTC also intends to study the impact of hospital consolidation on employee wages,” stated a news release.
Tale of Two COPAs
On its website, the Tennessee Department of Health describes a COPA as a “written approval by the Tennessee Department of Health (TDH) that governs a Cooperative Agreement (a merger) among two or more hospitals. A COPA provides state action immunity to the hospitals from state and federal antitrust laws by replacing competition with state regulation and Active Supervision. The goal of the COPA process is to protect the interests of the public in the region affected and the State.”
However, in its news release, the FTC described COPAs as “regulatory regimes adopted by state governments intended to displace competition among healthcare providers,” and said that, “COPAs purport to immunize mergers and collaborations from antitrust scrutiny under the state action doctrine. FTC staff are engaged in an ongoing policy project to assess the effects of COPAs, which includes the study of COPAs recently approved for Ballad Health in Tennessee and Virginia, and Cabell Huntington Hospital in West Virginia.”
In its 32-page “Order to File Special Report,” the FTC required the two healthcare organizations to provide “aggregated patient billing and discharge data; health system employee wage data; and other information relevant for analyzing the health systems’ prices, quality, access, and innovation,” the news release states.
The five health insurers required to respond to the FTC’s order included:
Aetna, Inc.
Anthem, Inc.
BlueCross BlueShield of Tennessee
Cigna Corporation
United Healthcare
From these insurers, the FTC required “patient-level commercial claims data,” states the news release.
Is the FTC conducting a study to determine if mergers and acquisitions are giving pricing power to hospitals at the expense of health insurers and patients? The FTC said that it plans to report the study’s findings, as appropriate, and use information to better understand COPAs, inform advocacy, and guide states involved in COPAs, the news release states.
“In the big picture, the FTC is potentially looking out for buyers. In this case, the insurers are the buyers. It’s the health systems that, if the FTC concludes that COPAs are bad for consumers, it would be the hospitals that would stand to lose,” Jonathan Grossman, antitrust attorney and partner at international law firm Cozen O’Conner, told Modern Healthcare. (Photo copyright: Cozen O’Connor.)
What Are COPAs and Do They Circumvent Antitrust Laws?
In a statement, the American Hospital Association (AHA) said COPA laws allow merging providers to make agreements that “might otherwise be subject to antitrust scrutiny.” COPA laws are coming about, AHA added, due to the FTC’s “overly harsh treatment of efficiencies claims made by merging hospitals.”
Big Data Order from FTC
In its order, the FTC required the health systems, providers, and insurer to provide massive amounts of information by January 1, 2020, including:
Patient records related to admissions, outpatient visits, skilled nursing visits, hospice, and other care in the COPA market since Jan 1, 2011;
Billed charges, diagnosis codes, and insurance coverage for the records;
Inpatient admissions, Jan. 1, 2011 to the present, aggregated on a monthly basis;
Data computed separately for Medicaid, Medicare, commercial, and other patients;
Patient totals, their billed charges, and payment by insurers and patients;
Changes in prices since Jan 1, 2011, which Modern Healthcare said is an effort to find “efficiencies, cost savings, and benefits as a result of COPAs”;
Facilities the provider opened, closed, or expanded since Jan. 1, 2011;
Changes in ownership and select capital investments;
Copies of health plan contracts effective since Jan. 1, 2011;
Salary, hours, and benefits of each person employed since Jan. 1, 2011;
And more.
Should Clinical Laboratory Leaders Be Concerned?
Medical lab leaders within hospital multi-lab systems will want to take note of the FTC’s interest in so much information. It was just a few years ago when US Senators Chuck Grassley and Max Baucus asked medical laboratory testing companies and health insurers for similar information, notes a 2011 news release from the office of Iowa Senator Chuck Grassley. Dark Daily reported on this in a November 2011 e-briefing.
The lab testing companies were:
Quest Diagnostics Incorporated (NYSE:DGX)
Laboratory Corporation of America (NYSE:LH)
UnitedHealth Group, Inc. (NYSE:UNH)
Aetna, Inc. (NYSE:AET)
Cigna Corp. (NYSE:CI)
According to the news release, Senators Baucus and Grassley requested “information about a practice where insurers receive discounted pricing from labs in exchange for referrals, including testing for Medicare beneficiaries.” In the letters to the lab companies, the senators described this pricing practice as “pull-through.”
Lab leaders also may recall the federal Department of Health and Human Services (HHS) collecting payment data in 2011 from 50 state Medicaid programs as part of a report on Competitive Bidding for Medicare Part B clinical laboratory services.
Could the FTC’s data request lead to other agencies taking steps that limit how providers set prices and reach out to markets, including clinical laboratories?
Put Prices Out There, President Says
Perhaps all this data collection is about price transparency in healthcare. The Trump Administration took action on healthcare price and quality transparency through the Improving Price and Quality Transparency in American Healthcare executive order. Under the order, the CMS has released two rules requiring hospital pricing information to be publicly available, noted a statement by the HHS.
So, there is a lot of data being shared. It is likely the FTC will share data it collects with other federal healthcare regulatory bodies as well. Therefore, medical laboratory managers would be well advised to stay abreast of mergers and acquisitions in their markets and be ready for future information requests from federal authorities.
Urinary tract infection (UTI) is the second most common type of infection in the US, accounting for 10.5 million office visits per year and 50 percent of all Medicare hospital admissions. UTI is among the most common cause of bacterial infections in long-term care facility residents.
Effective treatment of a UTI is reliant upon the accurate identification of the pathogens and the correct choice of antibiotics. Although culture-based clinical laboratory testing methods remain the gold standard for diagnosing UTI in both research and clinical laboratories, the clinical utility of such methods continues to be called into question.
This white paper provides insights on the status of clinical utility of rapid molecular testing for UTI, describes settings where molecular testing for UTI is of high value to improving outcomes, details experiences of successful early adopters of this technology.
Find these, and many more business-critical insights in this White Paper:
Learn why a large number of Gram-negative and especially Gram-positive organisms cannot grow in typical culture-based testing conditions, leading to false negatives and missed organisms in a polymicrobial UTI
See a comparison study of traditional urine culture testing to multiplex polymerase chain reaction (PCR) molecular testing, run in parallel, showing that the molecular method found six additional polymicrobial cases for every one found using urine cultures
How, in addition to higher detection rates, PCR can provide results in as little as 6 hours, and may facilitate more appropriate and efficacious treatment that improves clinical care and outcomes
Why insurers and other payers are now acknowledging molecular diagnostic testing, which includes deoxyribonucleic acid-(DNA) or ribonucleic acid-(RNA) based analysis, and much more
White Paper Table of Contents
Chapter 1: Problems and Limitations of Culture-Based Testing for UTI in Contrast to Molecular Testing
Chapter 2: Recent Clinical Trials Focused on UTI Diagnostics Using Rapid Molecular Testing
Chapter 3: Reimbursement Trends and Cost Versus Value in Molecular Testing for UTI
CONCLUSION
Molecular tests are becoming more routine as diagnostic tools, with many now covered by Medicare and commercial insurers. Advantages of molecular tests based on PCR technology include their ability to identify uropathogens traditionally missed by culture-based tests.
Driven by urgent, unmet analytical and clinical care needs, the adoption of the rapid molecular test—particularly RT-PCR for urinary tract infection control and treatment—has important implications.
Find out how this innovative testing strategy could benefit your lab by downloading your FREE copy of “Molecular Testing for Urinary Tract Infection (UTI)” below.
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Coronavirus informatics companies are drawing clinical laboratory test data out of the shadows and into the light and compiling it into critical bioinformatics resources
What better example do we have that clinical laboratory test data is critical to population health than the current COVID-19 pandemic? Medical laboratory scientists, bioinformatics developers, and government healthcare leaders are using lab test data to track the disease’s rate of infection, and through information system dashboards, they are mapping and managing the spread of SARS-CoV-2, the coronavirus that causes the COVID-19 illness.
One such example is the CV19 Lab Testing Dashboard developed by hc1 in Indianapolis, which “integrates SARS-CoV-2 testing data from more than 20,000 testing locations across the country, updating every four hours with information on the number of tests performed and the number of positive and negative results along with demographic information like the gender and age of patients being tested,” noted an article by 360Dx titled, “SARS-CoV-2 Pandemic a Test Case for Role of Lab Data in Population Health.”
“This pandemic is putting a spotlight on how important lab data is,” Brad Bostic, Founder, Chairman, and CEO of hc1, told the Indianapolis Business Journal (IBJ). His bioinformatics firm developed the CV19 dashboard, which draws on data created by a healthcare coalition of commercial and health system clinical laboratories that use the company’s High-Value Care Platform for lab testing.
The CV19 Lab Testing dashboard is free and provides a Local Risk Index that enables public health and government agencies, and healthcare providers, to monitor escalation of infection rate at the county level and predict the need for resources, noted an hc1 news release.
“We can offer insights [about the outbreak] seven to 14 days ahead of when emergency rooms and intensive care units get bogged down,” Bostic told the IBJ.
The hc1 dashboard provides healthcare providers with:
Test data collected from 20,000 locations covering 50 states and 90% of counties;
Information updates within minutes of SARS-CoV-2-PCR test results;
Test data that are quickly shared through an intuitive interface;
Geographic maps of test results that enable insight on COVID-19 infection rates at single county or Public Use Microdata Area level;
Number of tests per day, as well as positive and negative results; and
Displays of positivity rates and aggregated demographic information, such as gender and age.
Geisinger Health Uses Dashboard, Clinical Lab 2.0
The use of medical laboratory tests results in pursuit of population health also illustrates the value of the Clinical Lab 2.0 model, noted 360Dx.
According to 360Dx, Geisinger Health System, a leader in Clinical Lab 2.0, employs informatics tools for population-centric (as opposed to patient-focused) analysis of its SARS-CoV-2 testing. The Pennsylvania-based healthcare system uses lab testing dashboards to:
Review laboratory results in aggregate;
See positivity rates per county; and
Note amount of testing from sites.
“We needed to make sure that everyone could see the amount of testing that was being done, where that testing was coming from, and the results of that testing in a much [clearer] way. We began by setting up dashboards,” Jordan Olson, MD (above), a clinical pathologist and Geisinger’s Division Chief of Clinical Pathology, Informatics and Quality, told 360Dx. [Photo copyright: Cardinal Health/Whitehat Communications.)
Clinical Lab 2.0, a Project Santa Fe initiative, is a “business model leveraging longitudinal data to produce actionable clinical insight driving better outcomes for patients, providers, and stakeholders,” states the nonprofit organization’s website.
Sonora Quest Laboratories in Arizona also uses a dashboard to support its front-line healthcare workers to mitigate the spread of COVID-19, stated a news release.
“Most data flowing into public sector sites is eight to 14 days old, which in the case of COVID-19, is too told to react. Public health action requires the most immediate data possible, including test orders and results as soon as they appear,” said Meghan Shapiro Hunter, Vice President of Operations, Hospital Laboratories, Sonora Quest Laboratories, in the news release.
Other Informatics Technology Tracking COVID-19 Pandemic
Medial EarlySign develops AlgoMarkers that “perform algorithmic processing of lab results, clinical, and EHR data to provide condition-specific, post-analytical, personalized patient risk assessment scores to physicians, population health managers, and healthcare teams,” according to the medical informatics company’s website.
Headquartered in Israel, Medial worked with Maccabi Healthcare Services to develop an AlgoMarker that clinical laboratories, healthcare systems, and life sciences companies can use to spot trends in COVID-19 patients and make disease predictions based on risk, gender, co-morbidities, and medications, noted 360Dx.
Medial EarlySign also developed AlgoMarker algorithms to foresee influenza complications. According to a news release, the algorithms work by flagging people according to:
medical parameters,
demographics,
hospital admissions,
medications,
smoking history,
past diagnoses, and
chronic conditions.
Clinical Laboratory Data Enters the Spotlight
For some time now, medical laboratory data have been supporting positive outcomes and improving patient health from behind the curtain, so to speak. However, that appears to be changing fast as bioinformatics and medical informatics companies compile data in compelling dashboards aimed at helping public officials and healthcare providers manage the spread of COVID-19.
Pathologists, clinical laboratory leaders, and informatics specialists may want to explore use of dashboards to support their population health and COVID-19 testing efforts.
Current events have highlighted the critical role of the hospital laboratory as the primary source of diagnostic information. And with legislation such as PAMA (Protecting Access to Medicare Act) reducing reimbursement, hospital laboratories must determine the best direction in defining the role of the laboratory and its value to the hospital or health system.
Unfortunately, the laboratory’s critical role in determining diagnoses and treatments also makes it vulnerable to abuse. Studies estimate that from 10% to 25% of all hospital-performed laboratory tests in the inpatient setting are not indicated. Additionally, an increasingly complex, ever-expanding set of diagnostic test options necessitates heightened awareness in order to choose the right laboratory test at the right time.
Laboratory stewardship responds to these problems by establishing a true collaboration and partnership between the organization’s clinical leadership and the laboratory, to the benefit of both.
This white paper – the third in a three-part series developed in collaboration with Mayo Clinic Laboratories and Change Healthcare – provides frontline perspective and commentary from experts and physicians on the application and value of decision support in the laboratory. It also includes early-adopter proof points from hospital laboratories that have successfully implemented third-party decision support to achieve their stewardship goals, including EHR interventions and ongoing monitoring of utilization.
This series aims to help clinical laboratory professionals like you understand the risks and requirements, as well as the clinical and financial benefits, of implementing a clinical decision support (CDS) system.
Find these, and many more business-critical insights in this White Paper:
Learn to define your lab’s specific stewardship goals and measure progress toward them using robust analytics tools, in order to compare provider behavior against evidence-based guidelines and equip your lab with the means to take control of test utilization
Understand clinically-grounded guidelines that you can apply in your lab to help address the now-prevalent problem of too much data and information for providers to consume, the result to the benefit of both patients and providers
Hear how one midwestern hospital identified that B-type natriuretic peptide (BNP) was frequently over-ordered on their wards, and the steps they took that led to a decline of 33%-43% in inappropriate BNP orders
Find out why looking at data at the facility level, then at the department level, then at the provider level is of greatest benefit to your lab, and much more
White Paper Table of Contents
Chapter 1: Taking Control of Test Utilization to Curb Clinical Laboratory Waste
Chapter 2: Reducing Variation in Laboratory Testing and Care Delivery
Chapter 3: Data from Lab Test Stewardship Using Third-Party Clinical Decision Support in the Hospital Laboratory
Case Study 1
Case Study 2
Case Study 3
CONCLUSION
A laboratory test stewardship program requires organizational attention, physician champions, meaningful data, and dedicated IT resources to enact changes—with decision support vital to driving a strategic stewardship initiative.
Moreover, as you, as a thought leader pursue the creation of a value-based laboratory, instead of a commoditized service, you will soon identify overutilization and inappropriate lab testing as areas to target for process improvement and cost savings, thus boosting your lab’s value and reinventing your role in your lab’s organization.
Learn what you need to know about these value-enhancing strategies by downloading your FREE copy of “Case Studies in Clinical Laboratory Test Stewardship” below.
Download the White Paper now by completing the form below.
Access to some white papers may require registration. In exchange for providing this free content, we may share your information with the companies whose content you choose to view. By accessing the white paper, you’re agreeing to our Terms of Service and Privacy Policy.
