With more study, the technique could lead to new precision medicine pathology diagnostics and clinical laboratory tests
Researchers at Yale University have devised a new pathology tool that utilizes barcode technology to map the spatial relationships of ribonucleic acid (RNA) and proteins. This will be of interest to histopathologists who are responsible for examining clinical laboratory tissue samples and helping physicians diagnose disease.
Called Patho-DBiT (pathology-compatible deterministic barcoding in tissue), the Yale scientists claim their new tool can completely examine RNA and possibly aid in the diagnoses and treatment of cancer.
The technology, according to a Yale news release, “is unique in that it has microfluidic devices that deliver barcodes into the tissue from two directions creating a unique 2D ‘mosaic’ of pixels, providing spatial information that could be used to inform the creation of patient-specific targeted therapies.”
“It’s the first time we can directly ‘see’ all kinds of RNA species, where they are and what they do, in clinical tissue samples,” said Rong Fan, PhD, Harold Hodgkinson professor of biomedical engineering and pathology at Yale and senior author of the study.
“I think it’s going to completely transform how we study the biology of humans in the future,” said Rong Fan, PhD (above), Harold Hodgkinson professor of biomedical engineering and pathology at Yale and senior author of the study, in a Yale news release. The discovery could lead to new clinical laboratory screening tests and diagnostics for cancer. (Photo copyright: Yale University.)
More Precise Cancer Diagnoses
“As a physician who has been diagnosing cancer, I was surprised by how much more I can see using this pathology tool,” said Mina Xu, MD, professor of pathology at Yale School of Medicine and one of the authors of the study. “I think this deep molecular dive is going to advance our understanding of tumor biology exponentially. I really look forward to delivering more precise and actionable diagnoses.”
According to the Yale study, the Patho-DBiT tool has many beneficial capabilities. They include:
Dissecting spatiotemporal dynamics of lymphomagenesis at the single-cell level.
FFPE tissue involves the fixation of tissues by utilizing formalin and embedding tissue samples in paraffin wax. This method allows for the long-term preservation of tissue morphology and cellular details and is commonly used in histopathology.
In the past, the RNA within FFPE samples have been susceptible to fragmentation during the paraffin-embedding process and degradation issues. These samples may also experience chemical modifications which could result in resistance to the enzymatic reactions necessary for proper sequencing.
“There are millions of these tissues that have been archived for so many years, but up until now, we didn’t have effective tools to investigate them at spatial level,” said the study’s first author Zhiliang Bai, PhD, a postdoctoral associate in Rong Fan’s lab at Yale. “RNA molecules in these tissues we’re looking at are highly fragmented and traditional methods can’t capture all the important information about them. It’s why we’re very excited about Patho-DBiT.”
Targeted Therapies
The team is encouraged by their research and the future potential for Patho-DBiT. They believe the technology may be useful in creating targeted therapies and helping understand the metamorphosis of low-grade tumors to more aggressive ones. They conceive their tool may assist in developing ways to prevent the progression of cancers.
“It is very exciting that Patho-DBiT-seq is also capable of generating spatial maps of noncoding RNA expression,” said Jun Lu, PhD, associate professor of genetics at Yale and another of the study’s authors. “Noncoding RNAs are often in regions of our genomes that were previously thought of as junk DNA, but now they are recognized as treasured players in biology and diseases such as cancer.”
The research included faculty members from several departments at Yale and was supported by the National Institutes of Health (NIH). The technology is now licensed to biotechnology company AtlasXomics of New Haven, Ct., for further development.
More research and studies are needed to validate the findings of this research, but the Patho-DBiT tool could prove to be useful for the preservation of tissue samples and become essential in the diagnoses and treatment of cancers.
Clinical laboratories should closely watch the Trump administration as it contemplates a court appeal, a revised LDT rulemaking, or abandoning the rule altogether
With a US District Court judge’s decision to vacate the Food and Drug Administration’s (FDA) rule on laboratory-developed tests (LDTs), perhaps the most intriguing aspect for clinical laboratories is what the next move will be by the federal government.
It’s hard to predict whether the administration of President Donald Trump will either appeal the judge’s decision, direct the FDA to come up with a new version of the rule that passes legal muster, or simply back off further scrutiny of LDTs.
Let’s look more closely at the options for clinical laboratory professionals to monitor.
US District Court Judge Sean Jordan, JD (above), vacated the federal Food and Drug Administration’s final rule to regulate laboratory-developed tests (LDTs) on March 31, 2025. In a lawsuit, the Association for Molecular Pathologists and the American Clinical Laboratory Association accused the FDA of overstepping its legal authority in issuing the LDT rule in 2024. The outcome of this ruling will affect clinical laboratories’ future development their own tests. (Photo copyright: Jackson Walker LLP.)
Will the Trump Administration Appeal the LDT Decision?
The FDA’s final rule—which came out in 2024 and was about to hit its first compliance milestone on May 6, 2025—had been discussed for at least 10 years prior, covering multiple presidential administrations. Because the final rule was published by the FDA under former President Joe Biden, it surprised some observers to see Trump’s Department of Justice defend the FDA’s right to implement the rule during oral arguments in February before Judge Sean Jordan in US District Court for the Eastern District of Texas.
That hearing was the culmination of a combined lawsuit from American Clinical Laboratory Association (ACLA) and the Association for Molecular Pathology (AMP) challenging the LDT rule. The suit sought summary judgment on the matter, which Jordan granted on March 31 in his decision to vacate the FDA’s rule.
“The Court vacates and sets aside, in its entirety, the FDA’s final rule titled Medical Devices; Laboratory Developed Tests,” Jordan wrote. “The Court remands this matter to the secretary of Health and Human Services for further consideration.”
Trump’s legal team set a precedent early in the president’s second term to aggressively challenge any court decisions that buck his authority. From that perspective, an appeal of the LDT judgment seems probable, although there is no official word yet about that.
Trump ran on an anti-regulatory, smaller government platform. In that sense, the DOJ’s defense of the FDA’s standing to carry out the LDT rule was a surprise.
Will the FDA Create a Revised Version of the LDT Rule?
The court sent the rule back to the FDA, which leaves the door open for the agency to construct and issue a new rule.
The clinical laboratory industry argued that LDTs should not be classified as medical devices, which the rule instead emphasized. That could be an area where a new version of the rule bends.
Congress could also step in here. For many years, a proposed bill known as the VALID Act (formally the Verifying Accurate Leading-Edge IVCT Development Act) was filed in the House of Representatives to increase LDT oversight.
But then—after the FDA’s LDT rule came out—the VALID Act looked to be the lesser of two evils to lab professionals. It’s possible labs and lawmakers could work out a new version of the VALID Act to avoid another potentially onerous FDA-issued rulemaking.
Will Trump and the FDA Do Nothing?
Even though it would go against the current pattern of challenging court decisions, the Trump administration could simply step back and choose to do nothing with the FDA’s vacated rule.
In that case, presumably LDTs would continue to be overseen by the Clinical Laboratory Improvement Amendments of 1988 (CLIA). The medical lab industry has long preferred to see CLIA reform as the pathway to regulating LDTs in the future rather than formal FDA involvement. The FDA referred to this arrangement as “enforcement discretion,” as LDT oversight has always been on the books at the FDA, but the agency deferred to CLIA for many years.
Of related interest was a news release last week from the federal Department of Health and Human Services (HHS) announcing a sweeping number of layoffs under its individual agencies. The FDA is slated to lose 3,500 employees, although the “reduction will not affect drug, medical device, or food reviewers, nor will it impact inspectors,” HHS noted in a fact sheet.
Revisiting an LDT rule that will require more reviewers and inspectors seems at odds with a shrinking FDA.
Clinical Labs Must Monitor the Near-term Future of LDTs
After coming out ahead in one of the biggest court showdowns in clinical lab history, medical laboratory scientists and industry leaders now must keep their eyes on the various avenues that LDT regulation could head down in the near future.
Watch for further analysis of the business implications of this court decision in The Dark Report.
Disclosures, mandated by the Affordable Care Act, provide a limited snapshot of claim denials
Claim denials have created financial headaches for virtually all healthcare providers, including clinical laboratories and anatomic pathology groups. Reliable data about denials is hard to come by, but a recent analysis by KFF (formerly the Kaiser Family Foundation) revealed that insurers selling plans on HealthCare.gov denied 19% of claims for in-network services in 2023, the latest year for which data is available.
This is the highest rate since 2015, when KFF began tracking the data, according to the analysis. Claim denials for out-of-network services were even higher, amounting to 37%.
Patients and doctors “are saying that it’s become an even bigger hassle in recent years than it has been in the past,” said Kaye Pestaina, JD, co-author of the report, in a video report from CNBC. Pestaina is a KFF vice president and director of the organization’s program on patient and consumer protection.
The analysis, released Jan. 27, noted that the Affordable Care Act (ACA) requires insurers to provide data about health plans to state and federal regulators as well as the public. “However, federal implementation of this requirement has so far been limited to qualified health plans (QHP) offered on the federally facilitated Marketplace (HealthCare.gov) and does not include QHPs offered on state-based Marketplaces or group health plans.”
“One thing that we’ve seen [when] surveying consumers across different insurance types is that they simply don’t know that they have an appeal right,” said Kaye Pestaina, JD (above), VP and director of KFF’s program on patient and consumer protection, in a video report from CNBC. “If appeals were used more often, it might operate as a check on carriers. From what we can see now, so few are appealed, so it’s not operating as a check.” Clinical laboratories and anatomic pathology groups don’t often see data about the rate of claims denials by payers made public. (Photo copyright: KFF.)
Scarce Information
The federal marketplace covers 32 states, which means that the data does not include the 18 other states or the District of Columbia, all of which have their own exchanges. Nor does it include employer-sponsored plans, Medicare Advantage plans, or Medicaid Managed Care plans.
“In the big picture, we’re still operating from a scarce amount of information about how carriers review claims,” Pestaina told the Minneapolis Star-Tribune.
Within this limited dataset, KFF found wide variation in denial rates among the parent companies of health plans. The companies with the highest rates were as follows:
Rates also varied by state, from a high of 34% in Alabama to a low of 6% in South Dakota. However, the report noted that these averages sometimes obscured wide variations within each state. For example, in Florida, the statewide average was 16%, but denial rates for individual insurers ranged from 8% to 54%.
In most cases, in-network denial rates did not vary much based on plan levels. Rates were 15% for Platinum plans, compared with 18% for Silver and Gold plans, and 19% for Bronze plans. The rate for catastrophic plans was 27%.
The data offered only limited insights about the reasons for claim denials. The federal Centers for Medicare and Medicaid Services (CMS), which administers the rules, requires plans to report denial reasons, but it allows for an “Other” category that accounts for the largest number of denials:
Other reason not listed – 34%
Administrative reason – 18%
Service excluded – 16%
Enrollee benefit limit reached – 12%
Lack of referral or prior authorization – 9%
Not medically necessary (excluding behavioral health) – 5%
Member not covered – 5%
Not medically necessary (behavioral health only) – 1%
“We hear anecdotal stories about certain treatments that are denied, that arguably should not have been denied,” Pestaina told the Star-Tribune. “How often is that happening? It’s difficult to come to a conclusion with the kind of ‘reason’ information we have here.”
Health Insurers Pushback
In addition to claim denials, CMS requires insurers to report the number of appeals once a claim has been denied.
“As in KFF’s previous analysis of federal claims denial data, we find that consumers rarely appeal denied claims and when they do, insurers usually uphold their original decision,” the report states.
In total, insurers on the federal exchange denied 73 million in-network claims. Among these, less than 1% (376,527) were appealed internally to the insurers, which upheld 56% of the denials.
The report notes that, in some cases, consumers have a right to an external appeal in which a third party reviews the claim. However, in a separate survey, KFF found that only 40% of all consumers, and 34% of Marketplace enrollees, were aware of that right.
Health insurers pushed back on KFF’s analysis. In a statement reported by the Star-Tribune, UnitedHealth Group described the numbers as “grossly misleading” because the dataset represents only 2% of total claims.
“Across UnitedHealthcare, we ultimately pay 98% of all claims received that are for eligible members, when submitted in a timely manner with complete, non-duplicate information,” the company stated. “For the 2% of claims that are not approved, the majority are instances where the services did not meet the benefit criteria established by the plan sponsor, such as the employer, state or Centers for Medicare and Medicaid Services.”
Move comes two-years post-acquisition and is the second such unionization of Labcorp hospital lab workers
In February, clinical laboratory staff at Providence Portland Hospital in Oregon landed a 77% vote to unionize, with its 114 members joining the Oregon Federation of Nurses and Health Professionals (OFNHP). The laboratory scientists had been employees of Providence before the Catholic Health chain outsourced its medical laboratory operations to Labcorp in 2023.
“We decided to unionize because we want to ensure a stable, well-trained, well-staffed medical laboratory is available to our community. By unionizing we can have a strong voice for our patients and ourselves, ensuring a positive future for healthcare in this region,” said medical laboratory scientist Allister Brister-Smith, laboratory services team lead, in an OFNHP news release.
“Since the transition with Labcorp, we’ve noticed an increase in workload, an increase in expectations, and more of a focus on volume and throughput. Providence was more focused on quality,” Brister-Smith told Northwest Labor Press.
“That lab performs the blood, stool, and tissue testing that doctors at Providence’s Portland hospital rely on to make treatment decisions,” Willamette Week noted, adding that both staff and patients have been bemoaning test result delays that have occurred since the May 2023 transition. “Several blamed short-staffing for the lines and delays.”
Labcorp has not commented on the news, Labor Press reported.
One of the 114 Labcorp clinical laboratory workers at Providence Portland Hospital in Oregon who voted in February to unionize. “We are tasked with running so many tests and serving so many patients that we are concerned over the future of the care and services we offer, and we know that a change is necessary,” the workers stated in an OFNHP news release. (Photo copyright: OFNHP.)
Lab Workers Taken by Surprise
The 2023 news of the Labcorp outsourcing damaged morale, Northwest Labor Press reported.
“Lab, typically, is a fairly profitable section for a healthcare system, so when they pulled us into a big meeting and our lab director who had been with us since that lab was created announced to us that Providence had elected to sell off some of the assets, we were all really taken by surprise,” Brister-Smith told Northwest Labor Press.
He noted that many employees were committed to Providence’s corporate values and had forged ahead through the COVID-19 pandemic. “Most people who’d been working there and stuck around through COVID were pretty committed to the mission of Providence. It was quite a shock, honestly, to be told that our jobs would be outsourced to a for-profit company,” Brister-Smith added.
The Providence lab is comprised of employees with two- or four-year degrees, all certified from the American Society for Clinical Pathology (ASCP). Brister-Smith told Northwest Labor Press that lack of pay raises paired with diminishing quality of benefits has discouraged additional talented staff from joining there and instead saw them headed to Oregon Health and Science University and Kaiser Permanente.
The lab workers decided that unionizing was the way to be heard. “We believe that our voice and our input on workflow and the amount of work and staffing can have a positive impact on the long-term future of patient care,” Brister-Smith said. “It’s very inspiring to see people be on the same page, wanting to have some degree of control in their lives.”
Prior Labcorp Worker Unionization
This latest unionization movement is the second local hospital system that saw a merger with Labcorp result in a union. Prior to this, Legacy Health lab workers from 12 locations in Oregon and Washington state joined the union, 435 employees strong. That group is in the midst of contract bargaining, Northwest Labor Press added.
The timing of the unionization comes at a tender time for Providence as they have just wrapped up a 46-day strike comprised of 5,000 of their staff, including doctors and nurses. The strike began on January 10 but followed more than a year’s worth of bargaining. The end result impacted staffing, patient safety, and wages, the Oregon Nurses Association reported.
While businesses generally have an aversion to unions, response from Labcorp has been nonexistent. Willamette Week reported that “Labcorp’s media office did not immediately respond to a request for comment. Nor did Providence spokespeople,” and at this time, no press releases exist from Labcorp on the matter.
Clinical laboratories should use this situation as an opportunity to ask questions about their own data privacy approaches
While the drama surrounding 23andMe’s bankruptcy announcement has taken the spotlight—cofounder Anne Wojcicki resigned as CEO so that she can attempt to be the top bidder for the company in bankruptcy court—the more interesting long-term debate for clinical laboratories may be about genetic data privacy.
The 20-year-old direct-to-consumer genetic testing company stated in an investor news release on March 23 that it would enter bankruptcy to get a better handle on operational and financial challenges.
In a post on LinkedIn, Wojcicki wrote, “If I am fortunate enough to secure the company’s assets through the restructuring process, I remain committed to our long-term vision of being a global leader in genetics and establishing genetics as a fundamental part of healthcare ecosystems worldwide.”
Wojcicki also heralded the 15 million people who sent in their samples and became customers. Many of them also agreed to clinical research based on those submissions. “What made so many of our innovations possible were the 85% of our customers who opted in to research,” she wrote.
“I have resigned as CEO of the company so I can be in the best position to pursue the company as an independent bidder,” said Anne Wojcicki (above), cofounder of 23andMe, wrote on LinkedIn. It remains to be seen how 23andMe’s bankruptcy will affect clinical laboratories. (Photo copyright: Wikimedia Commons.)
Customer Data Can Be Sold as an Asset During Bankruptcy
Those samples now find themselves in a murky area involving genetic data privacy. Will a court allow creditors to acquire that data as an asset to satisfy 23andMe’s financial obligations? And will people who gave samples to a company they presumably trusted be happy if that information ends up in other hands?
“Comprehensive data privacy legislation has been enacted across the United States and globally, including the California Consumer Privacy Act of 2018 and the European Union’s General Data Protection Regulation,” the Harvard Law Review noted in a March 2025 story about data assets during bankruptcy. “With this development has come a renewed focus on data privacy in bankruptcy, where a debtor is likely to sell its customer data to pay its debts.”
In fact, California Attorney General Rob Bonta, JD, urged residents in that state to consider the California law’s options in light of the bankruptcy announcement. “I remind Californians to consider invoking their rights and directing 23andMe to delete their data and destroy any samples of genetic material held by the company,” Bonta said in a statement.
The Harvard Law Review noted that federal law allows for the appointment of ombudsmen in bankruptcy cases to protect consumer data, but that approach “has been ineffective at meeting that goal.” There is no word at this early stage whether the 23andMe bankruptcy will involve an ombudsman.
How Did 23andMe End Up in Bankruptcy?
Business models and criminals helped push the once thriving 23andMe to the point of bankruptcy. The company in 2021 had a $6 billion market cap. As of close of business on March 24, 2025, the cap hovered just over $20 million.
One long-term issue: There was often no need for anyone to be a repeat customer of 23andMe once they purchased their initial direct-to-consumer genetic test. “It didn’t really have a continuing business model—once you’d paid for your DNA report, there was very little for you to return for,” the BBC reported on Nov. 2.
Clinical labs are clearly in a better position here, as in addition to one-off genetic tests, they offer many medical assays that need to happen dozens or more times over a patient’s life.
Also, 23andMe had a difficult time gaining momentum for its anonymized DNA database that clinical researchers could use, according to the BBC.
A year later, 23andMe agreed to pay $30 million to settle a lawsuit over the stolen data, Reuters reported. The hack accessed information for 6.9 million customers.
Clinical Laboratories Must Be Wary of Genetic Data Privacy
It’s not hard to imagine clinical laboratories that perform genetic testing finding themselves in a situation similar to 23andMe with genetic data privacy on the line because of a business transaction. Some clinical laboratories do go bankrupt, but a more common occurrence is for a lab to be bought out by a competitor or one of the large national laboratory companies.
Clinical lab leaders may want to ask themselves these questions about genetic data privacy:
If a lab’s genetic testing information changed owners, would that damage parties’ reputation in the community?
Is there a triage plan in place to deal with any customers who want their data erased prior to any acquisition or merger?
Watch for in-depth analysis about the implications to clinical labs from the 23andMe bankruptcy in an upcoming issue of The Dark Report. Not a subscriber? Try a 14-day free trial today.
Pathologists and clinical laboratories will play a key role in collecting the data needed to create a person’s digital twin
Digital twins is a promising new technology that is making a big impact in healthcare. This development is significant because clinical laboratory test results will be among the most important sets of data to go into the creation of a patient’s “digital twin.”
A digital twin is defined by IBM as “a virtual representation of an object or system designed to reflect a physical object accurately. It spans the object’s lifecycle, is updated from real-time data, and uses simulation, machine learning, and reasoning to help make decisions.”
“We define a digital twin for healthcare as a virtual representation of a person which allows dynamic simulation of potential treatment strategy, monitoring and prediction of health trajectory, and early intervention and prevention, based on multi-scale modeling of multi-modal data such as clinical, genetic, molecular, environmental, and social factors, etc.,” wrote the authors of a review article published in NPJ Digital Medicine titled, “Digital Twins for Health: A Scoping Review.”
“The concept of digital twin for health (DT4H) holds great promise to revolutionize the entire healthcare system, including management and delivery, disease treatment and prevention, and health well-being maintenance, ultimately improving human life,” wrote study lead Eva Katsoulakis, MD (above), clinical informaticist and radiation oncologist at Tampa General Hospital in Florida, et al, in a review article she and her team published in NPJ Digital Medicine. Clinical laboratory test data will be a key element in the creation of a patient’s digital twin. (Photo copyright: Tampa General Hospital.)
Development of Digital Twins
Something akin to digital twins was first used in 1960 at NASA when replicas of spacecrafts currently on a mission in space were duplicated and studied on Earth. In 1991, Michael Grieves introduced the concept to manufacturing while at University of Michigan’s College of Engineering. The technology was later coined “digital twins” by John Vickers, a principal technologist in advanced manufacturing at NASA in 2010, IBM noted.
The increased use of digital twins in healthcare has brought some brilliant advancements. Examples, as reported by Computer Weekly, include:
Surgery and treatment: Boston Children’s Hospital uses digital twins to examine the complexities of heart procedures in reference to oxygen, blood flow, and valve pressure. Real-time analysis helps with surgeries and treatments, allowing clear visualization at all angles.
Metabolic analysis to tackle kidney failures: Digital twins are being used in Singapore to “Replicate metabolic fluxes to predict chronic kidney disease in type 2 diabetes mellitus.” Doctors there hope to curb the spike of chronic kidney disease found in type 2 diabetes mellitus. Their country has seen cases double in the last 40 years.
Bacterial predictions, E. coli: Bacteria behavior is being analyzed in computational simulations as part of a Simulating Microbial Systems (SMS) program. Run by the US Defense Advanced Research Projects Agency, the “SMS seeks interdisciplinary, comprehensive, and integrated workflows to generate unknown parameters from new data to inform computational models that can predict E. coli.”
Full body data: Precisely personalized care is the goal of European Virtual Human Twins Initiative, a project from the European Commission. The group creates digital twins and updates them with an individual’s personal conditions and health information that shifts as they age, keeping prevention as a focal point.
Respiratory viral pathogens: The complexities and variety of causes behind respiratory infections makes it an ideal area for digital twins. Its use in hospital ICUs can help doctors consider pneumonia treatment outlooks and develop plans for spread of infection.
Pharmaceuticals: Many pharma companies are opting to use digital twins since drug development is highly expensive and animal testing does not always provide clear data compared to human testing. Examples include Orion Pharma, which paired with AstraZeneca and Bayer to create digital twins that “capture genetic and molecular interactions that causally drive clinical and physiological outcomes.” Immunology company, Sanofi, also is using digital twins as “an essential first step to improve efficacy and safety.”
Future of Digital Twins in Healthcare
While digital twin development within healthcare is still in early stages, it promises to pioneer much change.
“When you have this model, you can personalize with certain features, certain anatomy, then you can try things. In heart surgery, you can’t try 20 different things, you only have one shot,” Ellen Kuhl PhD, professor of engineering and bioengineering at Stanford University, told Computer Weekly.
As technology advances and personalized healthcare continues to trend, it is likely digital twins will have a long-term place in medical practices. Astute clinical laboratory professionals will watch the expansion of this trend, since lab data will play such a key role in its development.
