Regulatory agencies in UK and US have yet to address dangers inherent in customer misunderstanding of DTC medical laboratory genetic test results
Direct-to-consumer (DTC) medical laboratory genetic tests are gaining popularity across the globe. But recent research out of the United Kingdom questions the reliability of these tests. The study, according to The Guardian, found that “Over the counter genetic tests in the UK that assess the risk of cancer or heart problems fail to identify 89% of those in danger of getting killer diseases.”
According the PGS website, “each PGS in the catalog is consistently annotated with relevant metadata; including scoring files (variants, effect alleles/weights), annotations of how the PGS was developed and applied, and evaluations of their predictive performance.”
However, the researchers told The Guardian, “Polygenic risk scores performed poorly in population screening, individual risk prediction, and population risk stratification. Strong claims about the effect of polygenic risk scores on healthcare seem to be disproportionate to their performance.”
“Strong claims have been made about the potential of polygenic risk scores in medicine, but our study shows that this is not justified,” Aroon Hingorani, PhD (above), Professor of Genetic Epidemiology at UCL and lead author of the study, told The Guardian. “We found that, when held to the same standards as employed for other tests in medicine, polygenic risk scores performed poorly for prediction and screening across a range of common diseases.” Consumer misunderstanding of DTC medical laboratory genetic tests is a real danger. (Photo copyright: University College London.)
Polygenic Scores Not Beneficial to Cancer Screening
To complete their study, the UCL researchers compared PGS genetic risk data to conventional clinical laboratory testing methods and discovered some troubling results. They include:
On average, only 11% of individuals who developed a disease had been identified by the tests.
A 5% false positive rate where people were informed that they would get a disease within 10 years but did not.
PGS only identified 10% of people who later developed breast cancer.
The researchers state in their BMJ Medicine paper that polygenic risk scores are not the same as testing for certain gene mutations, which could be critical in screening for some cancers. They also wrote that discovering genetic variants associated with the risk for disease is still crucial for drug development.
“It has been suggested that polygenic risk scores could be introduced early on to help prevent breast cancer and heart disease but, in the examples we looked at, we found that the scores contributed little, if any, health benefit while adding cost and complexity,” research physician and epidemiologist Sir Nicholas Wald, FRS, FRCP, FMedSci, Professor of Preventive Medicine at UCL Institute of Health Informatics and co-author of the study, told the Jersey Evening Post.
“Our results build on evidence that indicates that polygenic risk scores do not have a role in public health screening programs,” Wald added.
“This research study rightly highlights that for many health conditions genetic risk scores alone may have limited usefulness, because other factors such as deprivation, lifestyles, and environment are also important,” clinical epidemiologist Raghib Ali, MD, CEO, Chief Investigator and Chief Medical Officer, Our Future Health UK, told The Guardian.
Our Future Health is a collaboration between public, non-profit, and private sectors to create the UK’s largest health research program. The researchers in this endeavor intend to recruit over five million volunteers and use polygenic risk scores to develop innovative ways to prevent, detect, and treat disease. This program is funded by the UK’s National Health System (NHS).
“[Our] research program will be developing integrated risk scores that will take in all the important risk factors,” Ali explained. “We hope these integrated risk scores can identify people more likely to develop diseases, but this is a relatively new area of science and there are still unanswered questions around it.”
Danger of Misunderstanding DTC Genetic Tests
Here in the US, there have been news stories in recent years about the unreliability of certain genetic tests. Dark Daily covered these stories in previous ebriefs. News stories about the unreliability of genetic tests, particularly those marketed directly to consumers, reveal the problems that existing regulatory schemes have yet to address.
In “Consumer Reports Identifies ‘Potential Pitfalls’ of Direct-to-Consumer Genetic Tests,” we covered CR’s findings that though clinical laboratory and pathology professionals understand the difference between a doctor-ordered genetic health risk (GHR) test and a direct-to-consumer (DTC) genetic test, the typical genetic test customer may not. And that, misunderstanding the results of a DTC at-home genetic test can lead to confusion, loss of privacy, and potential harm.
Scientific American also covered the dangers of DTC testing in “The Problem with Direct-to-Consumer Genetic Tests,” in which the author notes that “despite caveats in ads and on packages, users can fail to understand their limitations,” and that “consumer-grade products are easily misconstrued as appropriate medical tests and create false reassurances in patients who could be at legitimate risk.”
Most clinical laboratory managers and pathologists are probably not surprised that the research performed at UCL shows that there are still issues surrounding genetic tests, particularly those marketed directly to consumers. While direct-to-consumer DNA tests can have some benefits, at this time, they are not always the best option for individuals seeking information about their personal risk for hereditary diseases.
Ten year collaboration between Google and Harvard may lead to a deeper understanding of the brain and new clinical laboratory diagnostics
With all our anatomic pathology and clinical laboratory science, we still do not know that much about the structure of the brain. But now, scientists at Harvard University and Google Research studying the emerging field of connectomics have published a highly detailed 3D reconstruction of human brain tissue that allows visualization of neurons and their connections at unprecedented nanoscale resolutions.
Further investigation of the nano-connections within the human brain could lead to novel insights about the role specific proteins and molecules play in the function of the brain. Though it will likely be years down the road, data derived from this study could be used to develop new clinical laboratory diagnostic tests.
The data to generate the model came from Google’s use of artificial intelligence (AI) algorithms to color-code Harvard’s electron microscope imaging of a cubic millimeter of neural tissue—equivalent to a half-grain of rice—that was surgically removed from an epilepsy patient.
“That tiny square contains 57,000 cells, 230 millimeters of blood vessels, and 150 million synapses, all amounting to 1,400 terabytes of data,” according to the Harvard Gazette, which described the project as “the largest-ever dataset of human neural connections.”
“A terabyte is, for most people, gigantic, yet a fragment of a human brain—just a minuscule, teeny-weeny little bit of human brain—is still thousands of terabytes,” said neuroscientist Jeff W. Lichtman, MD, PhD, Jeremy R. Knowles Professor of Molecular and Cellular Biology, whose Lichtman Lab at Harvard University collaborated on the project with researchers from Google. The two labs have been working together for nearly 10 years on this project, the Harvard Gazette reported.
Lichtman’s lab focuses on the emerging field of connectomics, defined “as understanding how individual neurons are connected to one another to form functional networks,” said neurobiologist Wei-Chung Allen Lee, PhD, Assistant Professor of Neurology, Harvard Medical School, in an interview with Harvard Medical News. “The goal is to create connectomes—or detailed structural maps of connectivity—where we can see every neuron and every connection.” Lee was not involved with the Harvard/Google Research study.
“The human brain uses no more power than a dim incandescent light bulb, yet it can accomplish feats still not possible with the largest artificial computing systems,” wrote Google Research scientist Viren Jain, PhD (above), in a blog post. “To understand how requires a level of understanding more profound than knowing what part of the brain is responsible for what function. The field of connectomics aims to achieve this by precisely mapping how each cell is connected to others.” Google’s 10-year collaboration with Harvard University may lead to new clinical laboratory diagnostics. (Photo copyright: Google Research.)
Study Data and Tools Freely Available
Along with the Science paper, the researchers publicly released the data along with analytic and visualization tools. The study noted that the dataset “is large and incompletely scrutinized,” so the scientists are inviting other researchers to assist in improving the model.
“The ability for other researchers to proofread and refine this human brain connectome is one of many ways that we see the release of this paper and the associated tools as not only the culmination of 10 years of work, but the beginning of something new,” wrote Google Research scientist Viren Jain, PhD, in a blog post that included links to the online resources.
One of those tools—Neuroglancer—allows any user with a web browser to view 3D models of neurons, axons, synapses, dendrites, blood vessels, and other objects. Users can rotate the models in xyz dimensions.
Users with the requisite knowledge and skills can proofread and correct the models by signing up for a CAVE (Connectome Annotation Versioning Engine) account.
Researchers Found Several Surprises
To perform their study, Lichtman’s team cut the neural tissue into 5,000 slices, each approximately 30 nanometers thick, Jain explained in the blog post. They then used a multibeam scanning electron microscope to capture high-resolution images, a process that took 326 days.
Jain’s team at Google used AI tools to build the model. They “stitched and aligned the image data, reconstructed the three dimensional structure of each cell, including its axons and dendrites, identified synaptic connections, and classified cell types,” he explained.
Jain pointed to “several surprises” that the reconstruction revealed. For example, he noted that “96.5% of contacts between axons and their target cells have just one synapse.” However, he added, “we found a class of rare but extremely powerful synaptic connections in which a pair of neurons may be connected by more than 50 individual synapses.”
In their Science paper, the researchers suggest that “these powerful connections are not the result of chance, but rather that these pairs had a reason to be more strongly connected than is typical,” Jain wrote in the blog post. “Further study of these connections could reveal their functional role in the brain.”
Mysterious Structures
Another anomaly was the presence of “axon whorls,” as Jain described them, “beautiful but mysterious structures in which an axon wraps itself into complicated knots.”
Because the sample came from an epilepsy patient, Jain noted that the whorls could be connected to the disease or therapies or could be found in all brains.
“Given the scale and complexity of the dataset, we expect that there are many other novel structures and characteristics yet to be discovered,” he wrote. “These findings are the tip of the iceberg of what we expect connectomics will tell us about human brains.”
The researchers have a larger goal to create a comprehensive high-resolution map of a mouse’s brain, Harvard Medical News noted. This would contain approximately 1,000 times the data found in the 1-cubic-millimeter human sample.
Dark Daily has been tracking the different fields of “omics” for years, as research teams announce new findings and coin new areas of science and medicine to which “omics” is appended. Connectomics fits that description.
Though the Harvard/Google research is not likely to lead to diagnostic assays or clinical laboratory tests any time soon, it is an example of how advances in technologies are enabling researchers to investigate smaller and smaller elements within the human body.
Findings could lead to new biomarkers clinical laboratories would use for identifying cancer in patients and monitoring treatments
As DNA “dark matter” (the DNA sequences between genes) continues to be studied, researchers are learning that so-called “junk DNA” (non-functional DNA) may influence multiple health conditions and diseases including cancer. This will be of interest to pathologists and clinical laboratories engaged in cancer diagnosis and may lead to new non-invasive liquid biopsy methods for identifying cancer in blood draws.
This technique could enable non-invasive monitoring of cancer treatment and cancer diagnosis, Technology Networks noted.
“Our study shows that ARTEMIS can reveal genomewide repeat landscapes that reflect dramatic underlying changes in human cancers,” said study co-leader Akshaya Annapragada (above), an MD/PhD student at the Johns Hopkins University School of Medicine, in a news release. “By illuminating the so-called ‘dark genome,’ the work offers unique insights into the cancer genome and provides a proof-of-concept for the utility of genomewide repeat landscapes as tissue and blood-based biomarkers for cancer detection, characterization, and monitoring.” Clinical laboratories may soon have new biomarkers for the detection of cancer. (Photo copyright: Johns Hopkins University.)
Detecting Early Lung, Liver Cancer
Artemis is a Greek word meaning “hunting goddess.” For the Johns Hopkins researchers, ARTEMIS also describes a technique “to analyze junk DNA found in tumors” and which float in the bloodstream, Financial Times explained.
“It’s like a grand unveiling of what’s behind the curtain,” said geneticist Victor Velculescu, MD, PhD, Professor of Oncology and co-director of the Cancer Genetics and Epigenetics Program at Johns Hopkins Kimmel Cancer Center, in the news release.
“Until ARTEMIS, this dark matter of the genome was essentially ignored, but now we’re seeing that these repeats are not occurring randomly,” he added. “They end up being clustered around genes that are altered in cancer in a variety of different ways, providing the first glimpse that these sequences may be key to tumor development.”
ARTEMIS could “lead to new therapies, new diagnostics, and new screening approaches for cancer,” Velculescu noted.
Repeats of DNA Sequences Tough to Study
For some time technical limitations have hindered analysis of repetitive genomic sequences by scientists.
“Genetic changes in repetitive sequences are a hallmark of cancer and other diseases, but characterizing these has been challenging using standard sequencing approaches,” the study authors wrote in their Science Translational Medicine paper.
“We developed a de novok-mer (short sequences of DNA)-finding approach called ARTEMIS to identify repeat elements from whole-genome sequencing,” the researchers wrote.
The scientists put ARTEMIS to the test in laboratory experiments.
The first analysis involved 1,280 types of repeating genetic elements “in both normal and tumor tissues from 525 cancer patients” who participated in the Pan-Cancer Analysis of Whole Genomes (PCAWG), according to Technology Networks, which noted these findings:
A median of 807 altered elements were found in each tumor.
About two-thirds (820) had not “previously been found altered in human cancer.”
Second, the researchers explored “genomewide repeat element changes that were predictive of cancer,” by using machine learning to give each sample an ARTEMIS score, according to the Johns Hopkins news release.
The scoring detected “525 PCAWG participants’ tumors from the healthy tissues with a high performance” overall Area Under the Curve (AUC) score of 0.96 (perfect score being 1.0) “across all cancer types analyzed,” the Johns Hopkins’ release states.
Liquid Biopsy Deployed
The scientists then used liquid biopsies to determine ARTEMIS’ ability to noninvasively diagnose cancer. Researchers used blood samples from:
ARTEMIS classified patients with lung cancer with an AUC of 0.82.
ARTEMIS detected people with liver cancer, as compared to others with cirrhosis or viral hepatitis, with a score of AUC 0.87.
Finally, the scientists used their “ARTEMIS blood test” to find the origin of tumors in patients with cancer. They reported their technique was 78% accurate in discovering tumor tissue sources among 12 tumor types.
“These analyses reveal widespread changes in repeat landscapes of human cancers and provide an approach for their detection and characterization that could benefit early detection and disease monitoring of patients with cancer,” the researchers wrote in Science Translational Medicine.
Large Clinical Trials Planned
Velculescu said more research is planned, including larger clinical trials.
“While still at an early stage, this research demonstrates how some cancers could be diagnosed earlier by detecting tumor-specific changes in cells collected from blood samples,” Hattie Brooks, PhD, Research Information Manager, Cancer Research UK (CRUK), told Financial Times.
Should ARTEMIS prove to be a viable, non-invasive blood test for cancer, it could provide pathologists and clinical laboratories with new biomarkers and the opportunity to work with oncologists to promptly diagnosis cancer and monitor patients’ response to treatment.
Findings could lead to clinical laboratory tests that help physicians identify microbes lacking in the microbiomes of their Parkinson patients
Microbiologists and clinical laboratory scientists know that gut microbiome can be involved in the development of Parkinson’s disease, a progressive neurological disorder that affects the nervous system due to damage caused to nerve cells in the brain. There is no cure for the illness. But a new treatment developed by researchers at the VIB Center for Inflammation Research at the University of Ghent in Belgium, may help to alleviate the symptoms.
During a clinical trial, VIB Center for Inflammation Research (VIB-IRC) scientists discovered that fecal microbiota transplantation (FMT), also known as a stool transplant, can improve motor skills in some Parkinson’s patients, according to Neuroscience News.
Parkinson’s disease (PD) develops when a protein called alpha-synuclein misfolds and forms into bundled clusters damaging nerve cells in the brain that produce dopamine. These formations, which are believed to appear in the gastrointestinal wall in the early stages of PD, then reach the brain via the vagus nerve leading to typical PD symptoms in patients.
“Our study provides promising hints that FMT can be a valuable new treatment for Parkinson’s disease,” Roosmarijn Vandenbroucke, PhD (above), Principal Investigator, VIB-UGent Center for Inflammation Research and full professor, UGent Department of Biomedical molecular biology, Faculty of Sciences, told Neuroscience News. “More research is needed, but it offers a potentially safe, effective, and cost-effective way to improve symptoms and quality of life for millions of people with Parkinson’s disease worldwide.” Clinical laboratories will likely be involved in identifying the best microbes for the FMT treatments. (Photo copyright: University of Ghent.)
Correlation between Gut Microbiome and Neurogenerative Disease
To perform their clinical study—referred to as GUT-PARFECT—the IRC researchers first recruited patients with early-stage PD and healthy donors who provided stool samples to the Ghent Stool Bank. The PD patients received the healthy stool via a tube inserted into the nose which led directly into the small intestine.
The FMT procedures were performed on 46 patients with PD between December 2020 and December 2021. The participants in this group ranged in ages from 50 to 65. There were 24 PD patients in the placebo group, and a total of 22 donors provided the healthy stool. Clinical evaluations were performed at baseline, three, six, and 12 months.
After 12 months, the group that received the transplants showed a reduction in symptoms compared to the placebo group. Their motor score on the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) improved by a mean of 5.8 points. The improvement registered on the same scale for the placebo group was 2.7 points.
Developed in the 1980s, the MDS-UPDRS is a scale utilized to evaluate various aspects of PD by measuring patient responses via a questionnaire rating several issues (such as cognitive impairment, apathy, depression, and anxiousness) common in PD patients from normal to severe. It is divided into four parts:
Part I: Non-motor experiences of daily living.
Part II: Motor experiences of daily living.
Part III: Motor examination.
Part IV: Motor complications.
During the final six months of the research, the improvement in motor symptoms became even greater. To the VIB-IRC researchers this implied that an FMT may have long-lasting effects on PD patients. The FMT study group also experienced less constipation, a condition that can be bothersome for some PD patients.
“Our results are really encouraging!” said the study’s first author, Arnout Bruggeman, MD, PhD student, VIB-UGent Center for Inflammation Research, in a UGent News release. “After twelve months, participants who received the healthy donor stool transplant showed a significant improvement in their motor score, the most important measure for Parkinson’s symptoms.”
Findings Could Lead to Other Targeted Therapies for PD
The VIB-IRC researchers believe there is a correlation between the gut microbiome and Parkinson’s disease.
“Our findings suggested a single FMT induced mild, but long-lasting beneficial effects on motor symptoms in patients with early-stage PD. These findings highlight the potential of modulating the gut microbiome as a therapeutic approach and warrant a further exploration of FMT in larger cohorts of patients with PD in various disease stages,” the IRC researchers wrote in eClinicalMedicine.
“Our next step is to obtain funding to determine which bacteria have a positive influence. This could lead to the development of a ‘bacterial pill’ or other targeted therapy that could replace FMT in the future,” Debby Laukens, PhD, Associate Professor, Ghent University, told Neuroscience News.
According to the Parkinson’s Foundation website, nearly one million people in the US live with PD. It is second only to Alzheimer’s disease in the category of neurodegenerative diseases.
More research and studies are needed before the VIB-IRC’s stool transplant treatment can be used in clinical care. As researchers learn more about which specific strains of bacteria are doing the beneficial work in PD patients, that data could eventually lead to clinical laboratory tests performed to help physicians identify which microbes are lacking in the microbiomes of their PD patients, and if fecal transplants could help those patients.
Only about a third of the hospitals surveyed are in full compliance with giving public access to prices, the watchdog group contends, but the AHA disputes its methodology
It’s been almost four years since the Centers for Medicare and Medicaid Services (CMS) enacted its Hospital Price Transparency rule which requires hospitals—including their medical laboratories—to make their prices available and easily accessible to the public. But according to a 2024 report from PatientRightsAdvocate.org (PRA), just 34.5% of reviewed hospitals are fully compliant with the transparency rule. That’s a slight decrease from the 36% compliance rate the PRA listed in its 2023 report, the watchdog group stated in a blog post.
Released on Feb. 29, this was the group’s sixth semi-annual hospital price transparency report since the CMS rule took effect in 2021.
The rule “requires hospitals to post all prices online, easily accessible and searchable, in the form of (i) a single machine-readable standard charges file for all items, services, and drugs by all payers and all plans, the de-identified minimum and maximum negotiated rates, and all discounted cash prices, as well as (ii) prices for the 300 most common shoppable services either as a consumer-friendly standard charges display listing actual prices or, alternatively, as a price estimator tool,” the report states.
The required viewable prices are to be for, among others, medical imaging, clinical laboratory testing, and outpatient procedures such as a colonoscopies, etc.
“With full transparency, consumers can benefit from competition to make informed decisions, protect from overcharges, billing errors, and fraud, and lower their costs,” the report states. “Employer and union plans can use pricing and claims data to improve their plan designs and direct members to lower cost, high-quality facilities. However, continued noncompliance impedes this ability.”
At any time, the US Department of Justice (DOJ) could decide to file charges against a hospital or a clinical laboratory for not posting their prices on their websites in compliance with the federal rule. Such an action by DOJ officials would be to specifically put the entire industry on notice that there will be consequences for non-compliance.
The PRA’s report provides hospitals and clinical laboratories with a reminder that consumer watchdogs are also monitoring compliance.
“Our comprehensive study of 2,000 hospitals indicates nearly two-thirds (65.5%) of hospitals reviewed continue failing to fully comply with the rule, yet the Centers for Medicare and Medicaid Services (CMS) has only fined fourteen hospitals for noncompliance out of the thousands found to not be meeting all of the rule’s requirements. When hospitals don’t post their prices, they can charge whatever they want,” wrote PRA Founder and Chairman Cynthia Fisher (above) in a letter to President Biden. Hospital medical laboratories are also required to post their prices for tests. (Photo copyright: PatientRightsAdvocate.org.)
To compile their report, PRA analysts examined the websites of 2,000 US hospitals between September 3, 2023, and January 13, 2023, and found that 1,311, or 65.5%, were not in full compliance, mostly due to “missing or significantly incomplete pricing data,” the report states.
More than 6,000 licensed hospitals operate in the US, the report notes. The group said it focused on hospitals owned by the largest US health systems.
Among the notable findings:
The 2023 report found that 98% of Kaiser Permanente’s 42 hospitals were in full compliance with the rule, but in the 2024 study, none were compliant because the hospitals began posting multiple files instead of a single file.
In total, 103 hospitals rated as noncompliant in the previous report were found to be compliant in the new analysis. Conversely, 135 hospitals previously rated as compliant were listed as noncompliant in the 2024 report.
The report lauded three hospitals for posting “exemplary files” that were “easily accessible, downloadable, machine-readable, and including all negotiated rates by payer and plan.” Those were Cape Cod Hospital in Hyannis, Mass.; Christus Santa Rosa Medical Center in San Antonio; and UW Health University Hospital in Madison, Wis.
In its discussion of the findings, PRA called on CMS to step up enforcement of the pricing transparency rule. The group also wants the government to close what it describes as the “estimator tool loophole,” which allows hospitals to list non-binding price estimates and price ranges instead of concrete prices.
“Price estimator tools do not achieve the goals of price transparency policy and fundamentally undermine the intent of the regulations,” the PRA’s report contends.
In response to the 2023 PRA report, AHA Group Vice President for Public Policy Molly Smith issued the following statement, “Once again, Patient Rights Advocate has put out a report that blatantly misconstrues, ignores, and mischaracterizes hospitals’ compliance with federal price transparency regulations. The AHA has repeatedly debunked point-by-point Patient Rights Advocate’s intentionally misleading ‘reports’ on price transparency.”
Citing CMS data, Smith said that as of 2022, 70% of US hospitals had complied with two key federal rules:
One requiring hospitals to post machine-readable files with pricing information.
The other mandating a list of prices for at least 300 “shoppable” services.
More than 80% of hospitals had complied with at least one of the rules, she contended in an AHA press release.
Speaking to the New Orleans Times-Picayune, PRA Founder and Chairman Cynthia Fisher said her group performs a more in-depth study of pricing data compared with CMS.
“They did not do a comprehensive review,” she told the publication. “We do a deep dive for full compliance.”
The PRA study came on the heels of a January report from Turquoise Health that offered a rosier assessment of hospital compliance, albeit with different criteria. According to the Turquoise report, as of Dec. 15, 2023:
90.7% of 6,357 US hospitals had posted machine-readable files,
83.1% posted information about negotiated rates, and
77.3% posted cash rates.
The Turquoise Health end-to-end price transparency platform uses a 5-point system to rate the quality of hospitals’ machine-readable files and said that more than 50% scored five stars. Clinical laboratory managers and pathologists may find it timely to review their lab organization’s compliance with this federal price transparency rule.
