Lawsuits filed by whistleblowers, doctors, and hospitals allege EHR software used by hospitals, clinical laboratories, and medical offices may ‘pose danger to patients’
Where have all the federal incentives for meaningful use of health information technology (HIT) gone? Pathologists and clinical laboratory leaders caught up in medical error investigations are not the only healthcare providers asking this question.
Now, an ongoing investigation by Fortune and Kaiser Health News (KHN) indicates some EHR software vendors and healthcare providers were paid hundreds of millions of dollars in federal subsidies that they should not have received. Furthermore, EHRs are apparently associated with thousands of mistakes and medical errors, the Fortune and KHN investigation revealed.
In “Electronic Health Records Creating a ‘New Era’ of Health Care Fraud,” KHN wrote that “The federal government funneled billions in subsidies to software vendors who overstated or deceived the government about what their products could do, according to whistleblowers.”
However, MIPS and MACRA are only recent updates to the original federal legislation that launched the drive to incentivize hospitals, physicians and other providers to adopt and use EHR systems that met defined criteria. It was the $787-billion stimulus bill—the American Recovery and Reinvestment Act of 2009 (ARRA)—that actually defined the incentive program and allotted an initial $17 billion specifically to encourage adoption of EHR systems.
Now, more than a decade later, there is growing evidence
that many EHR vendors and providers took advantage of the EHR incentives
without meeting both the intent and requirements of this federal program. For
example, government reviewers found that some providers and vendors collected
their federal EHR subsidy payments and then “gamed” the system by programming the
software to appear to meet incentive criteria, even though it had not, Becker’s
Hospital Review reported.
“The only problem (with software certification) is that it presupposed that the [EHR] product [certified by a] vendor would be the same product it sold. It presupposes that people will go into the certification process and participate in good faith,” John Halamka, MD, a Professor of Medicine at Harvard Medical School, Chief Information Officer at Beth Israel Deaconess Medical Center, and Co-Chairman of the national HIT Standards Committee, told KHN.
According to Fortune–KHN study findings:
Lawsuits filed by “dozens” of whistleblowers, doctors, and hospitals allege EHR software used by hospitals and medical offices may “pose danger to patients;”
Some of the $38 billion in federal EHR subsidies went to companies that “deceived the government about the quality of their products;”
Three EHR vendors were part of settlement deals totaling $357 million with the US Department of Justice (DOJ);
28% of doctors and 5% of hospitals who said they met government standards for EHR adoption and use were later found to have not done so, audits showed;
$941 million in inappropriately released EHR subsidies were recovered by federal officials.
Investigation Suggests EHRs Linked to Medical Errors
In one case, a patient had gone to the emergency room with severe headaches and a high fever. During the diagnostic process, a doctor performed a spinal tap to rule out meningitis, an inflammation of the tissue covering the brain and spinal cord. Later, through the hospital’s new EHR system, an infectious disease specialist ordered a clinical laboratory test to check the spinal fluid for viruses, including herpes simplex. Unfortunately, the lab test order did not make it to the lab.
A lawsuit later filed by the patient stated that the hospital’s EHR didn’t “interface” with the hospital medical laboratory, delaying results of the lab test, resulting in brain damage due to herpes encephalitis, Fortune reported. In the lawsuit, the patient alleges the missed order meant he did not receive an antiviral medication (aciclovir) that could have minimized the brain damage.
The graphic above is based on data from the Kaiser Family Foundation (KFF) study. In the first article of its investigative series, Fortune wrote, “KHN and Fortune examined more than two dozen medical negligence cases that have alleged that EHRs either contributed to injuries, had been improperly altered, or were withheld from patients to conceal substandard care.” Some of these errors involved delayed clinical laboratory test results, resulting in severe patient injury. (Graphic copyright: Kaiser Family Foundation.)
After interviewing 100 doctors, patients, IT experts, health
policy leaders, attorneys and government officials, Fortune–KHN found:
“Thousands of deaths, serious injuries, and near misses tied to software glitches, user errors, or other flaws;”
EHRs enabled “upcoding” or inflating a bill instead of improving billing;
A “disconnected patchwork” instead of an electronic superhighway.
The researchers found that “The usability of current EHR systems received a grade of F by physician users when evaluated using a standardized metric of technology usability. A strong dose-response relationship between EHR usability and the odds of burnout was observed.”
In their survey of 870 doctors, the researchers asked for a ranking of EHR system usability on a scale of 0 to 100. The mean score of 45.9 was deemed an “F,” Becker’s Hospital Review explained.
The researchers suggested that “Given the association
between EHR usability and physician burnout, improving EHR usability may be an
important approach to help reduce health care professional burnout.”
That could be the understatement of the decade.
“It is a national imperative to overhaul the design and use of EHRs and reframe the technology to focus primarily on its most critical function—helping physicians care for their patients. Significantly enhancing EHR usability is key,” said Patrice Harris, MD, President of the American Medical Association, in a statement.
All is not well with the EHR segment of healthcare
information technology, as attested to by the number of lawsuits, complaints,
and news accounts of patient harm due to misperforming EHR systems and user
error. Because of the growing number of lawsuits involving the function and use
of different EHR products, clinical laboratory leaders would be wise to ensure
their EHR interfaces to healthcare providers function correctly and check them
often.
Non-hospital-owned ambulatory care providers continue to take revenue from hospitals, as more patients choose urgent care centers and other options over emergency rooms
Thanks to the popularity of urgent care clinics and other non-hospital-based ambulatory care providers, the year-over-year growth in the number of hospital outpatient visits has been on the decline for decades. Dark Daily has covered this trend in many e-briefings over the years. But now, for the first time since 1983, outpatient visits fell below the previous year among more than 6,000 hospitals surveyed by the American Hospital Association (AHA).
This is an important event, because anything that affects a hospital’s
revenue also affects that hospital’s medical laboratories and everyone
connected to it. The decline, according to the AHA, is primarily due to decreasing
visits to hospital emergency rooms. ERs provide significant revenue for
hospitals. Fewer ER visits means less clinical laboratory test ordering, fewer
image study requests, and may mean lower financial revenues overall.
The AHA released the findings in its “2020 Hospital Statistics Report.” The data show that outpatient visits to hospitals have decreased one year to the next for the first time in 35 years.
The AHA surveyed 6,146 hospitals located throughout the
nation. In 2017, those hospitals recorded a total of 880.5 million outpatient
visits. In 2018, those same hospitals delivered 879.6 million outpatient visits,
a reduction of 0.09% over the previous year.
That survey result marked the first time since 1983 that there was a decrease in outpatient visits from one year to the next, Modern Healthcare reported. The article goes on to state that the AHA’s report, “highlights the fact that patients are increasingly gravitating toward the countless disruptors that tout more convenient, cheaper options for primary care, urgent care, and even emergency care.”
The graphic above, taken from the American Hospital Association’s “2020 Hospital Statistics Report,” illustrates the decline in hospital outpatient visits since 1983. Besides studying ER visits, the AHA also surveyed hospital-owned ambulatory surgery centers, outpatient clinics, and walk-in clinics. Visits to those outpatient facilities remained stable, according to the AHA, or rose slightly from the previous year. Nevertheless, a decrease in visits to ERs means fewer clinical laboratory test and image study requests. (Graphic copyright: American Hospital Association.)
More Options for Receiving Healthcare Services
One of the main reasons for the decrease in hospital
outpatient visits is that patients have more options when seeking care. The
rise in the number of urgent care and walk-in clinics has provided healthcare
consumers with more convenient, less expensive options than traditional
hospital settings.
“We’re pivoting to a new business model in healthcare, with a much more pluralistic delivery system with many, many more consumer options,” Ken Kaufman, Chairman of management consulting firm Kaufman Hall, told Modern Healthcare. “Which, of course, is exactly the same thing that’s happening in other parts of the economy. I think it’s very important that especially the major health systems recognize this and realize they have to compete against it.”
Gap Between Inpatient and Outpatient Revenue Narrows
The AHA’s survey also found that, though there were fewer
outpatient visits to emergency rooms, the surveyed hospitals’ net outpatient
revenue actually increased by 4.5% from 2017 to 2018, and that the gap between
outpatient and inpatient revenue for hospitals continues to narrow.
In 2017, outpatient revenue for the hospitals was $494
billion, while inpatient revenue was $508 billion. That meant that total
outpatient revenue was 97% of the new inpatient revenue for 2017. In 2018, that
percentage was 95%; however, in 2016, it was 92%.
“I don’t know that I can speculate as to when they will converge, but the trend lines seem to be getting closer,” Aaron Wesolowski, Vice President, Policy Research, Analytics, and Strategy at AHA, told Modern Healthcare.
Though Outpatient Revenues Increased, Hospital Profits
Decreased
The AHA survey found that, overall, hospital profits
decreased by 5.2% when comparing 2017 to 2018. In 2017, the hospitals reported
a combined profit of $88 billion, but only a profit of $83.5 billion for
2018.
Wesolowski noted that the most likely reasons for the decrease
in profits were due to:
Continued lower reimbursements from public
payers;
The shift from inpatient to outpatient care;
Increasing labor costs; and
Increasing costs for drugs and supplies.
AHA annual hospital surveys also collected aggregate data
regarding payments and costs associated with hospital care to beneficiaries of
Medicare and Medicaid services. Those
surveys found that:
Combined underpayments to hospitals totaled
$76.6 billion in 2018, which included a shortfall of $56.9 billion for Medicare
and $19.7 billion for Medicaid.
In 2018, 66% of surveyed hospitals received
Medicare payments less than cost and 61% received Medicaid payments less than
cost.
Hospitals received payment of only 87 cents for
every dollar spent caring for Medicare patients in 2018.
Hospitals received payment of 89 cents for every
dollar spent caring for Medicaid patients in 2018.
Additionally, according the “AHA Hospital Statistics 2020 Edition,” the total number of admissions for all US hospitals in 2018 was 36,353,946, while total expenses for all US hospitals in the same year totaled an astronomical $1,112,207,387,000.
With more convenient and less expensive options for medical
care are becoming increasingly available to consumers, competition for
outpatients will continue to increase. In the interest of producing new revenue
sources—or just maintaining existing revenues—it would be prudent for clinical
laboratory leaders to develop strategies for providing lab testing services to
the growing number of outpatient ambulatory healthcare providers that compete
with hospital ERs.
Strategists agree that big tech is disrupting healthcare,
so how will clinical laboratories and anatomic pathology groups serve virtual
healthcare customers?
Visionary XPRIZE founder Peter Diamandis, MD, sees big tech as “the doctor of the future.” In an interview with Fast Company promoting his new book, “The Future Is Faster Than You Think,” Diamandis, who is the Executive Chairman of the XPRIZE Foundation, said that the healthcare industry is “phenomenally broken” and that Apple, Amazon, and Google could do “a thousandfold” better job.
Diamandis, who also founded Singularity University, a global learning and innovation community that uses exponential technologies to tackle worldwide challenges, according to its website, said, “We’re going to see Apple and Amazon and Google and all the data-driven companies that are in our homes right now become our healthcare providers.”
If this prediction becomes reality, it will bring significant changes in the traditional ways that consumers and patients have selected providers and access healthcare services. In turn, this will require all clinical laboratories and pathology groups to develop business strategies in response to these developments.
Amazon Arrives in Healthcare Markets
Several widely-publicized business initiatives by Amazon, Google, and Apple substantiate these predictions. According to an Amazon blog, healthcare insurers, providers, and pharmacy benefit managers are already operating HIPAA-eligible Amazon Alexa for:
Alexa also enables HIPAA-compliant blood glucose updates as part of the Livongo for Diabetes program. “Our members now have the ability to hear their last blood glucose check by simply asking Alexa,” said Jennifer Schneider, MD, President of Livongo, a digital health company, in a news release.
And Cigna’s “Answers By Cigna” Alexa “skill” gives members who install the option responses to 150 commonly asked health insurance questions, explained a Cigna news release.
“Google plans to disrupt healthcare and use data and artificial intelligence,” Toby Cosgrove, Executive Advisor to the Google Cloud team and former Cleveland Clinic President, told B2B information platform PYMNTs.com.
PYMNTs speculated that Google, which recently acquired Fitbit, could be aiming at connecting consumers’ Fitbit fitness watch data with their electronic health records (EHRs).
“Ultimately what’s best is human and AI collaboratively,” Peter Diamandis, MD, founder of XPRIZE Foundation and Singularity University told Fast Company. “But I think for reading x-rays, MRIs, CT scans, genome data, and so forth, that once we put human ego aside, machine learning is a much better way to do that.” (Photo copyright: SALT.)
Apple Works with Insurers, Integrating Health Data
The Apple Watch health app also enables people to access medical laboratory test results and vaccination records, and “sync up” information with some hospitals, Business Insider explained.
Virtual Care, a Payer Priority: Survey
Should healthcare providers feel threatened by the tech giants? Not necessarily. However, employers and payers surveyed by the National Business Group on Health (NBGH), an employer advocacy organization, said they want to see more virtual care solutions, a news release stated.
“One of the challenges employers face in managing their healthcare costs is that healthcare is delivered locally, and change is not scalable. It’s a market-by-market effort,” said Brian Marcotte, President and CEO of the NBGH, in the news release. “Employers are turning to market-specific solutions to drive meaningful changes in the healthcare delivery system.
“Virtual care solutions bring healthcare to the consumer
rather than the consumer to healthcare,” Marcotte continue. “They continue to
gain momentum as employers seek different ways to deliver cost effective,
quality healthcare while improving access and the consumer experience.”
“In AI, there are three trends to watch,” said health strategist Ted Schwab (above) while speaking at the 2019 Executive War College. “The first major AI trend will affect clinical laboratories and pathologists. It involves how diagnosis will be done on the Internet and via telehealth. The second AI trend is care delivery, such as what we’ve seen with Amazon’s Alexa—you should know that Amazon’s business strategy is to disrupt healthcare. And the third AI trend involves biological engineering,” he concluded. (Photo copyright: Dark Daily.)
“If you use Google in the United States to check symptoms,
you’ll get five-million to 11-million hits,” Schwab told The Dark Report.
“Clearly, there’s plenty of talk about symptom checkers, and if you go online
now, you’ll find 350 different electronic applications that will give you
medical advice—meaning you’ll get a diagnosis over the internet. These
applications are winding their way somewhere through the regulatory process.
“The FDA just released a report saying it plans to regulate
internet doctors, not telehealth doctors and not virtual doctors,” he
continued. “Instead, they’re going to regulate machines. This news is
significant because, today, within an hour of receiving emergency care, 45% of
Americans have googled their condition, so the cat is out of the bag as it
pertains to us going online for our medical care.”
Be Proactive, Not Reactive, Health Leaders Say
Healthcare leaders need to work on improving access to primary care, instead of becoming defensive or reactive to tech companies, several healthcare CEOs told Becker’s Hospital Review.
Clinical laboratory leaders are advised to keep an eye on
these virtual healthcare trends and be open to assisting doctors engaged in
telehealth services and online diagnostic activities.
Referral-kickback and bribery schemes that included medical laboratory tests bilked private insurers and government health plans out of $150 million over six-year period
Andrew Hillman, former co-owner of Next Health LLC, a network of drug and genetic-testing laboratories and pharmacies based in Dallas, who pleaded guilty in 2018 to violating federal anti-kickback laws, has been sentenced to 66 months in prison and ordered to pay $3 million in restitution for his role in Medicare fraud, money laundering, healthcare bribes, and doctor kickbacks, reported The Dallas Morning News.
Dark Daily’s sister publication The Dark Report (TDR) previously reported on the federal lawsuit filed by UnitedHealthcare (NYSE:UNH) against Next Health in 2017 for allegedly running fraudulent drug testing and doctor kickback schemes from 2012-2018 in Dallas.
The two owners of Next Health, Andrew Hillman and Semyon Narosov, pleaded guilty to “multiple medical kickback schemes in Dallas in which doctors were paid to steer patients to certain hospitals,” The Dallas Morning News reported. One scheme involved clinical laboratory test specimens that “were sent to the Next Health labs for a battery of unnecessary and expensive tests under the guise of a wellness study, court records say, and doctors were paid kickbacks for referring patients.”
Hillman and Narosov admitted to defrauding both government and private insurance through the phony “wellness” program and through a separate physician kickback scheme in which doctors were paid to refer patients to the now-closed Forest Park Medical Center (FPMC) in Dallas. In court filings, they admitted that “Next Health billed private and government health insurance plans more than $450 million between 2012 and 2018 and collected about $150 million in fraudulent proceeds,” Dallas Morning News reported.
Though Hillman’s guilty plea could have resulted in a
15-year prison sentence, he cooperated with federal investigators in the FPMC
bribery scheme investigation and for that he received a reduced sentence.
Narosov also pleaded guilty in both cases, but he has not yet been
sentenced.
Clinical laboratories were at the center of the Next Health money laundering scheme, which involved multiple shell companies, limited liability companies (LLCs) and umbrella corporations to shield the unlawful conduct from detection. And it worked for five years until 2017, when UnitedHealthcare (UHC) filed a $100 million federal lawsuit against Dallas-based Next Health and its subsidiary labs:
Additionally, two individuals also were charged: former Next
Health marketing representative Erik Bugen and Kirk Zajac.
As outlined in the lawsuit, UnitedHealthcare initially uncovered the fraud during a review of routine medical laboratory test claims to identify abnormal testing activity. Upon a deeper investigation, the insurer discovered an array of bribes and kickbacks and other potential crimes. In one illicit arrangement, Next Health sales consultants provided $50 gift cards to people who provided urine samples in a Whataburger bathroom as part of the “wellness study.”
Clinical laboratory specimens were sent to Next Health
laboratories for “multiple unnecessary and expensive drug tests that were later
billed to United and its customers,” the lawsuit states.
The lawsuit contends the defendants:
Paid bribes and kickbacks to referral sources,
including physicians, sober homes and sales consultants, in exchange for
requesting out-of-network lab services;
Billed for lab services that were not ordered by
medical providers;
Inflated claims by utilizing standing protocols
for blanket testing, regardless of patients’ medical histories, clinical
conditions, or needs;
Billed for services the defendants did not
perform; and
Billed charges the defendants never intended to
collect from patients.
UnitedHealthcare Director of Communications Matthew Rodriguez (above) told the Dallas Morning News, “UnitedHealthcare has taken an active role in recent years in prosecuting instances of lab fraud, and this decision will continue to shine light on companies engaged in inappropriate lab services that put patients at risk and drive up costs.” He said the nation’s largest single health insurer will continue to go after clinical laboratories they suspect may be defrauding the healthcare industry. [Photo copyright: BusinessWire.]
Other Healthcare Frauds and Kickback Schemes Against
UnitedHealthcare
As TDR detailed in “Allegations in UHC Health Insurance Fraud Case Involve Multiple Defendants,” January 22, 2018, Hillman and several other defendants were not novices in devising healthcare kickback schemes. TDR noted the UnitedHealthcare lawsuit was the “visible tip of a large iceberg,” with the insurance giant the latest victim in a pattern of potential fraud and abuse that extended back almost a decade. Included in the laundry list of other allegedly illegal schemes was one distinctly similar to the Next Health fraud.
A year earlier, the US Attorney’s Office of the Northern District of Texas brought indictments against 21 persons affiliated with the physician-owned Forest Park Medical Center in Dallas. Next Health’s Hillman and Narosov were also included in that indictment, as well as 38 subsidiaries of U.S. Health Group, an earlier incarnation of Next Health.
The pair’s ownership and management positions within Next
Health and its subsidiaries created “an illegal scheme that was similar to the
one in place at Forrest [sic] Park,” UnitedHealthcare stated in its complaint.
The indictment alleged FPMC paid approximately $40 million
in bribes and kickbacks to physicians, recruiters, and others in exchange for
referring lucrative patients—particularly those with high-reimbursing, private
health insurance or benefits under certain federal programs—to the
out-of-network hospital.
Hillman, who was among 10 defendants who pleaded guilty before the FPMC case went to trial, testified for the government, the federal Department of Justice (DOJ) said in a statement.
In addition, seven others were convicted of conspiracy to pay or receive healthcare bribes.
“The verdict in the Forest Park case is a reminder to healthcare practitioners across the District that patients—not payments—should guide decisions about how and where doctors administer treatment,” US Attorney for the Northern District of Texas Erin Nealy Cox, JD, said in a press release announcing the guilty verdicts.
US District Court Judge John Parker,
JD, who served as US Attorney for the Northern District of Texas when the
FPMC indictments were handed down, explained the impact of fraud on the
healthcare system.
“Medical providers who enrich themselves through bribes and kickbacks are not only perverting our critical healthcare system, but they are committing a serious crime,” Parker said in a statement announcing the FPMC indictments. “Massive, multi-faceted schemes such as this one, built on illegal financial relationships, drive up the cost of healthcare for everyone and must be stopped.”
The lesson for clinical laboratory leaders is that vigilance
is key to spotting bad actors who wish to defraud the healthcare system. This
is double critical at a same time when labs are under increased scrutiny from
payers, federal and state regulators, and law enforcement.
Pathologists can be paid for their role in identifying and recruiting patients for basket studies and reporting results of medical laboratory tests
Anatomic
pathologists who biopsy, report, and diagnosis cancer will benefit from a
better understanding of basket
studies and their application in developing cancer treatment therapies. Such
studies can lead to more documentation of the effectiveness of various therapies
for cancers with specific gene
signatures.
The US
National Library of Clinical Medicine defines basket studies as “a new sort
of clinical studies to identify patients with the same kind of mutations and
treat them with the same drug, irrespective of their specific cancer type. In
basket studies, depending on the mutation types, patients are classified into ‘baskets.’
Targeted therapies that block that mutation are then identified and assigned to
baskets where patients are treated accordingly.”
“Historically, cancer clinical trials have been centered on the treatment of cancer based on the anatomic location in the body, like breast cancer or brain cancer or lung cancer. A basket study is a novel trial design that includes patients with a certain molecular aberration regardless of location or tissue of origin of cancer in the body. The genomic revolution in oncology has fueled these studies,” Vivek Subbiah, MD, Associate Professor and Medical Director, Clinical Center for Targeted Therapy ( Phase 1 trials program), at the University of Texas MD Anderson Cancer Center in Houston, told Cancer Therapy Advisor. (Photo copyright: MD Anderson Cancer Center.)
Basket Studies Get Results
During a basket study, researchers may find that a drug’s
effectiveness at targeting “a genetic mutation at one site can also treat the
same genetic mutation in cancer in another area of the body,” noted Pharmacy
Times, which also pointed out basket studies are often starting points for
larger oncology trials about drugs.
For example, it was a basket study which found that vemurafenib (marketed as
Zelboraf), intended for treatment of V600E, a mutation of the BRAF gene, may also treat Erdheim-Chester
disease (a rare blood disorder) in patients who have the BRAF V600 gene
mutation, Pharmacy Times reported.
Additionally, the US Food and Drug Administration’s approval
of the cancer drug Vitrakvi (larotrectinib), an oral TRK
inhibitor, marked the first treatment to receive a “tumor-agnostic
indication at time of initial FDA approval,” a Bayer
news release stated. The drug’s efficacy, Pharmacy Times noted, was
found in a “pivotal” basket study.
Basket Studies, a Master Protocol Trial Design
The basket study technique is an example of a master protocol trial design. The FDA defines a master protocol as “a protocol designed with multiple substudies, which may have different objectives and involves coordinated efforts to evaluate one or more investigational drugs in one or more disease subtypes within the overall trial structure. A master protocol may be used to conduct the trial(s) for exploratory purposes or to support a marketing application and can be structured to evaluate, in parallel, different drugs compared to their respective controls or to a single common control.”
Other master protocols include umbrella studies and platform
studies, according to Cancer Therapy Advisor, which noted that each
master protocol trial design has its own unique objectives:
Umbrella studies look at the effectiveness of
multiple drugs on one type of cancer;
Platform trials investigate the effectiveness of
multiple therapies on one disease on an ongoing basis; and
Basket studies focus on the effectiveness of one
therapy on patients with different cancers based on a biomarker.
“In contrast to traditional trials designs, where a single
drug is tested in a single disease population in one clinical trial, master
protocols use a single infrastructure, trial design, and protocol to
simultaneously evaluate multiple drugs and or disease populations in multiple
substudies, allowing for efficient and accelerated drug development,” states
the FDA draft guidance, “Master
Protocols: Efficient Clinical Trial Design Strategies to Expedite Development
of Oncology Drugs and Biologics.”
Final FDA guidance on master protocols design is expected early in 2020, an FDA spokesperson told Cancer Therapy Advisor.
While master protocol studies show promise, they generally
have small sample sizes, noted researchers of a study published in the journal Trials.
And some researchers have ethical concerns about basket studies.
Nevertheless, basket studies appear to hold promise for precision medicine.
Anatomic pathologists may want to follow some of them or find a way to get
involved through identifying clinical laboratory tests and reporting the results.
The scientist also employed machine learning “to gauge how easily accessible genes are for transcription” in research that could lead to new clinical laboratory diagnostic tests
Anatomic pathologists and clinical laboratories are of course familiar with the biological science of genomics, which, among other things, has been used to map the human genome. But did you know that a three-dimensional (3D) map of a genome has been created and that it is helping scientists understand how DNA regulates its organization—and why?
The achievement took place at St. Jude Children’s Research Hospital (St. Jude) in Memphis, Tenn. Scientists there created “the first 3D map of a mouse genome” to study “the way cells organize their genomes during development,” a St. Jude news release noted.
Some experts predict that this new approach to understanding how changes happen in a genome could eventually provide new insights that anatomic pathologists and clinical laboratory scientists could find useful when working with physicians to diagnose patients and using the test results to identify the most appropriate therapy for those patients.
In addition to 3D modeling, the researchers applied machine learning to data from multiple sources to see how the organization of the genome changed at different times during development. “The changes are not random, but part of the developmental program of cells,” Dyer said in the news release.
The St. Jude study focused on the rod cells in a mouse retina. That may seem like a narrow scope, but there are more than 8,000 genes involved in retinal development in mice, during which those genes are either turned on or off.
To see what was happening among the cells, the researchers used HI-C analysis, an aspect of ultra-deep chromosome conformation capture, in situ. They found that the loops in the DNA bring together regions of the genome, allowing them to interact in specific ways.
Until this study, how those interactions took place was a
mystery.
“Understanding the way cells organize their genomes during development will help us to understand their ability to respond to stress, injury and disease,”Michael Dyer, PhD (above), Chair of St. Jude’s Developmental Neurobiology Department, co-leader of the Developmental Biology and Solid Tumor Program, and Investigator at Howard Hughes Medical Institute (HHMI), said in the news release. (Photo copyright: St. Jude Children’s Research Hospital.)
The scientists also discovered there were DNA promoters, which encourage gene expression, and also DNA enhancers that increase the likelihood gene expression will occur.
“The research also included the first report of a powerful regulator of gene expression, a super enhancer, that worked in a specific cell at a specific stage of development,” the news release states. “The finding is important because the super enhancers can be hijacked in developmental cancers of the brain and other organs.”
St. Jude goes on to state, “In this study, the scientists determined that when a core regulatory circuit super-enhancer for the VSX2 gene was deleted, an entire class of neurons (bipolar neurons) was eliminated. No other defects were identified. Deletion of the VSX2 gene causes many more defects in retinal development, so the super-enhancer is highly specific to bipolar neurons.”
The St. Jude researchers developed a genetic mouse model of
the defect that scientists are using to study neural circuits in the retina,
the news release states.
Research Technologist Victoria Honnell (left); Developmental Neurobiologist Jackie Norrie, PhD (center); and Postdoctoral Researcher Marybeth Lupo, PhD (right), work in the St. Jude clinical laboratory of Michael Dyer, PhD, using 3D genomic mapping to study gene regulation during development and disease. (Photo copyright: St. Jude Children’s Research Hospital.)
DNA Loops May Matter to Pathology Sooner Rather than
Later
Previous researcher studies primarily used genomic sequencing technology to locate and investigate alterations in genes that lead to disease. In the St. Jude study, the researchers examined how DNA is packaged. If the DNA of a single cell could be stretched out, it would be more than six feet long. To fit into the nucleus of a cell, DNA is looped and bundled into a microscopic package. The St. Jude scientists determined that how these loops are organized regulates how the cell functions and develops.
Scientists around the world will continue studying how the loops in DNA impact gene regulation and how that affects the gene’s response to disease. At St. Jude Children’s Research Hospital, Dyer and his colleagues “used the same approach to create a 3D genomic map of the mouse cerebellum, a brain structure where medulloblastoma can develop. Medulloblastoma is the most common malignant pediatric brain tumor,” noted the St. Jude’s news release.
In addition to providing an understanding of how genes
function, these 3D studies are providing valuable insight into how some
diseases develop and mature. While nascent research such as this may not impact
pathologists and clinical laboratories at the moment, it’s not a stretch to
think that this work may lead to greater understanding of the pathology of
diseases in the near future.
