Researchers find genome sequencing identified conditions missed by standard newborn screening programs that use common clinical laboratory tests
Interim results from a large ongoing pilot study suggest that genome sequencing of newborn children may be more effective than traditional clinical laboratory screening for detection of early-onset genetic conditions. The researchers also found that parents were highly receptive to the idea of performing the sequencing on their newborns.
“The results show us that genome sequencing can radically improve children’s medical care,” said study co-author Joshua Milner, MD, chief of allergy, immunology, and rheumatology services at NewYork-Presbyterian/Columbia University Irving Medical Center, in a Columbia University press release.
“Genome sequencing allows us to detect things that cause serious illness and take action to prevent those illnesses in a significant number of children, not just a few rare cases. It should be instituted as the next standard for newborn screening because it can detect so much more than current methods,” said study co-author Joshua Milner, MD (above), chief of allergy, immunology, and rheumatology services at NewYork-Presbyterian/Columbia University Irving Medical Center, in a press release. Study finding suggest genetic sequencing can be more effective than clinical laboratory screening tests for early detection of genetic disorders. (Photo copyright: Columbia University.)
GUARDIAN Study Details
For the pilot study, the researchers sought consent from 5,555 families, with 4,000 (72%) agreeing to participate. The babies studied were born between September 2022 and July 2023. At that time, the researchers screened for 156 treatable conditions. Parents could also choose to add a panel of 99 neurodevelopmental disorders that do not have treatments, but where “affected children may benefit from early intervention,” the press release notes.
The total—255 genetic tests—included the 50 conditions in the standard Newborn Screening Program as a quality control, principal investigator Wendy Chung, MD, PhD, told Healio.
Among the 4,000 participants, 147 children (3.7%) screened positive for one of the conditions. Further testing confirmed diagnoses in 120 children. “Only 10 of these children were detected through standard screening,” the Columbia press release states.
The vast majority—92 of 120 children—were diagnosed with glucose-6-phosphate dehydrogenase (G6PD) deficiency. “G6PD is not included in traditional screening but individuals with G6PD deficiency can have moderate to life-threatening reactions to certain foods and medications which can easily be prevented by avoiding them,” the press release notes.
Screening for Previously Unscreened Treatable Disorders
The New York State Department of Health mandates free Newborn Screening (NBS) in which a blood sample is collected for testing, generally 24 to 36 hours after birth. The test screens for 50 disorders.
Genome sequencing, however, “offers an additional method to improve screening for conditions already included in NBS and to add those that cannot be readily screened because there is no biomarker currently detectable in dried blood spots,” the GUARDIAN researchers wrote in JAMA.
In the GUARDIAN study, families planning to give birth at an NYP hospital can authorize the researchers to perform genome sequencing of the same dried blood spots to screen for additional pre-selected genetic conditions. At present, the study screens for more than 450 conditions, according to the study website.
“It would be prohibitive to screen for all these diseases with standard testing, but with genomic screening, there’s minimal extra cost when adding a condition,” said study co-author Jordan Orange MD, PhD, chair of pediatrics at Columbia University’s Vagelos College of Physicians and Surgeons and physician-in-chief of NewYork-Presbyterian’s Morgan Stanley Children’s Hospital, in the Columbia press release. “We can screen for treatable disorders that we never thought of screening for before.”
GeneDX, which performs the genomic sequencing for GUARDIAN, issued a press release in which it listed other conditions that are not part of the standard screening. These include Long QT syndrome, which the company described as “a rare heart condition that may cause Sudden Infant Death Syndrome (SIDS) and can be treated with beta-blockers.”
GUARDIAN also detected conditions that came up as false negatives in the standard screening, Chung told Healio. One baby had a genetic variant that causes severe combined immunodeficiency disorder (SCID), a rare and often-fatal condition. Chung said that the genomic sequencing identified the condition while the standard newborn screening missed it.
“We know that a bone marrow transplant is a cure for these children, but safety and success are the highest when the transplant occurs in the first few months of life, before the child starts developing infections or other symptoms,” Milner said in the Columbia press release. “Only because of the genomic screening were we able to identify this child in time.”
Excluding the G6PD cases, the positive screening rate was 0.6%, twice the rate of standard screening. As of last November, more than 12,000 babies had been enrolled in the study. The researchers hope to enroll 100,000.
Advances in Genomic Sequencing Bring Benefits to NBS
“In my practice, I’ve seen many patients who’ve spent years going from doctor to doctor with symptoms that no one can explain. But by the time they receive a diagnosis, the window to best manage the disease has usually passed,” said Chung in the Columbia University press release.
Looking ahead, Chung told Healio that she’d like to expand outside of New York, “in part for generalizability to demonstrate that this is something that could be done with our national public health newborn screening system.”
She’d also like to cut the turnaround time from the current three weeks to one week, she said. And she’d like to drive down the cost.
“Families and pediatricians don’t need to go through those diagnostic odysseys anymore with the genomic technology we now have. We can make the diagnosis at birth,” she said.
The GUARDIAN study shows how advances in genetic testing are moving fast enough that the point has been reached where the classic clinical laboratory methodologies for newborn screening used for decades are becoming outmoded because of the superior performance/cost of genome sequencing.
List also includes precision oncology, liquid biopsies, and early diagnosis of pancreatic cancer
Pathologists and clinical laboratory managers will be interested to learn that in a recently updated article the World Economic Forum (WEF) identified a dozen important recent breakthroughs in the ongoing fight to defeat cancer, including some related to pathology and clinical laboratory diagnostics.
The article noted that approximately 10 million people die each year from cancer. “Death rates from cancer were falling before the pandemic,” the authors wrote. “But COVID-19 caused a big backlog in diagnosis and treatment.”
The Swiss-based non-profit is best known for its annual meeting of corporate and government leaders in Davos, Switzerland. Healthcare is one of 10 WEF “centers” focusing on specific global issues.
Here are four advances identified by WEF that should be of particular interest to clinical laboratory leaders. The remaining advances will be covered in part two of this ebrief on Wednesday.
“Our study represents a major leap in cancer screening, combining the precision of protein-based biomarkers with the efficiency of sex-specific analysis,” said Novelna founder and CEO Ashkan Afshin, MD, ScD (above), in a company press release. “We’re not only looking at a more effective way of detecting cancer early but also at a cost-effective solution that can be implemented on a large scale.” The 12 breakthroughs listed in the World Economic Forum’s updated article will likely lead to new clinical laboratory screening tests for multiple types of cancer. (Photo copyright: Novelna.)
Novelna’s Early-Stage Cancer Test
Novelna, a biotech startup in Palo Alto, Calif., says it has developed a clinical laboratory blood test that can detect 18 early-stage cancers, including brain, breast, cervical, colorectal, lung, pancreatic, and uterine cancers, according to a press release.
In a small “proof of concept” study, scientists at the company reported that the test identified 93% of stage 1 cancers among men with 99% specificity and 90% sensitivity. Among women, the test identified 84% of stage 1 cancers with 85% sensitivity and 99% specificity.
The researchers collected plasma samples from 440 individuals diagnosed with cancers and measured more than 3,000 proteins. They identified 10 proteins in men and 10 in women that correlated highly with early-stage cancers.
“By themselves, each individual protein was only moderately accurate at picking up early stage disease, but when combined with the other proteins in a panel they were highly accurate,” states a BMJ Oncology press release.
The company says the test can be manufactured for less than $100.
“While further validation in larger population cohorts is necessary, we anticipate that our test will pave the way for more efficient, accurate, and accessible cancer screening,” said Novelna founder and CEO Ashkan Afshin, MD, ScD, in the company press release.
Precision Oncology
According to the National Institutes of Health’s “Promise of Precision Medicine” web page, “Researchers are now identifying the molecular fingerprints of various cancers and using them to divide cancer’s once-broad categories into far more precise types and subtypes. They are also discovering that cancers that develop in totally different parts of the body can sometimes, on a molecular level, have a lot in common. From this new perspective emerges an exciting era in cancer research called precision oncology, in which doctors are choosing treatments based on the DNA signature of an individual patient’s tumor.”
“These advanced sequencing technologies not only extend lifespans and improve cure rates for cancer patients through application to early screening; in the field of cancer diagnosis and monitoring they can also assist in the formulation of personalized clinical diagnostics and treatment plans, as well as allow doctors to accurately relocate the follow-up development of cancer patients after the primary treatment,” Wang wrote.
Based in China, Genetron Health describes itself as a “leading precision oncology platform company” with products and services related to cancer screening, diagnosis, and monitoring.
Liquid and Synthetic Biopsies
Liquid biopsies, in which blood or urine samples are analyzed for presence of biomarkers, provide an “easier and less invasive” alternative to conventional surgical biopsies for cancer diagnosis, the WEF article notes.
These tests allow clinicians to “pin down the disease subtype, identify the appropriate treatment and closely track patient response, adjusting course, if necessary, as each case requires—precision medicine in action,” wrote Merck Group CEO Belén Garijo, MD, in an earlier WEF commentary.
The WEF article also highlighted “synthetic biopsy” technology developed by Earli, Inc., a company based in Redwood City, Calif.
As explained in a Wired story, “Earli’s approach essentially forces the cancer to reveal itself. Bioengineered DNA is injected into the body. When it enters cancer cells, it forces them to produce a synthetic biomarker not normally found in humans.”
The biomarker can be detected in blood or breath tests, Wired noted. A radioactive tracer is used to determine the cancer’s location in the body.
“Pancreatic cancer is one of the deadliest cancers,” the WEF article notes. “It is rarely diagnosed before it starts to spread and has a survival rate of less than 5% over five years.”
The test is based on a technology known as high-conductance dielectrophoresis (DEP), according to a UC San Diego press release. “It detects extracellular vesicles (EVs), which contain tumor proteins that are released into circulation by cancer cells as part of a poorly understood intercellular communication network,” the press release states. “Artificial intelligence-enabled protein marker analysis is then used to predict the likelihood of malignancy.”
The test detected 95.5% of stage 1 pancreatic cancers, 74.4% of stage 1 ovarian cancers, and 73.1% of pathologic stage 1A lethally aggressive serous ovarian adenocarcinomas, they wrote.
“These results are five times more accurate in detecting early-stage cancer than current liquid biopsy multi-cancer detection tests,” said co-senior author Scott M. Lippman, MD.
Look to Dark Daily’s ebrief on Wednesday for the remainder of breakthroughs the World Economic Forum identifies as top advancements in the fight to defeat cancer.
Clinical laboratories and pathology groups may soon have new assays for diagnosis, treatment identification, patient monitoring
It’s here at last! The human Y chromosome now has a full and complete sequence. This achievement by an international team of genetic researchers is expected to open the door to significant insights in how variants and mutations in the Y chromosome are involved in various diseases and health conditions. In turn, these insights could lead to new diagnostic assays for use by clinical laboratories and pathology groups.
Pathologists and clinical laboratories involved in genetic research will understand the significance of this accomplishment. The full Y chromosome sequence “fills in gaps across more than 50% of the Y chromosome’s length, [and] uncovers important genomic features with implications for fertility, such as factors in sperm production,” SciTechDaily noted.
This breakthrough will make it possible for other research teams to gain further understanding of the functions of the Y chromosome and how specific gene variants and mutations contribute to specific health conditions and diseases. In turn, knowledge of those genetic sequences and mutations would give clinical laboratories the assays that help diagnosis, identify relevant therapies, and monitor a patient’s progress.
“When you find variation that you haven’t seen before, the hope is always that those genomic variants will be important for understanding human health,” said Adam Phillippy, PhD, a senior investigator and head of the Genome Informatics Section at the National Human Genome Research Institute, in a press release. Clinical laboratories and anatomic pathology groups may soon have new assays based on the T2T study findings. (Photo copyright: National Human Genome Research Institute.)
Study Background and Recognition
Revolutionary thinking by the Telomere-to-Telomere (T2T) scientists led to the team’s breakthrough. The researchers “applied new DNA sequencing technologies and sequence assembly methods, as well as knowledge gained from generating the first gapless sequences for the other 23 human chromosomes,” SciTechDaily reported.
In 1977, the first complete genome of an organism was sequenced. Thus began the commencement of sequencing technology research. Twenty years ago the first human genome sequence was completed. The result was thanks to years of work through the preferred “chain termination” (aka, Sanger Sequencing) method developed by Fred Sanger and a $2.7 billion contribution from the Human Genome Project, according to a study published in the African Journal of Laboratory Medicine (AJLM).
By 2005, a new era in genomic sequencing emerged. Scientists now employed a technique called pyrosequencing and the change had great benefits. “Massively parallel or next-generation sequencing (NGS) technologies eliminated the need for multiple personnel working on a genome by automating DNA cleavage, amplification, and parallel short-read sequencing on a single instrument, thereby lowering costs and increasing throughput,” the AJLM paper noted.
The new technique brought great results. “Next-generation sequencing technologies have made sequencing much easier, faster and cheaper than Sanger sequencing,” the AJLM study authors noted.
The changes allowed more sequencing to be completed. Nevertheless, more than half of the Y chromosome sequence was still unknown until the new findings from the T2T study, SciTechDaily reported.
Why the TDT Breakthrough Is So Important
“The biggest surprise was how organized the repeats are,” said Adam Phillippy, PhD, a senior investigator and head of the NHGRI. “We didn’t know what exactly made up the missing sequence. It could have been very chaotic, but instead, nearly half of the chromosome is made of alternating blocks of two specific repeating sequences known as satellite DNA. It makes a beautiful, quilt-like pattern.”
Much can be gained in knowing more about the Y chromosome. Along with the X chromosome, it is significant in sexual development. Additionally, current research is showing that genes on the Y chromosome are linked to the risk and severity of cancer.
Might What Comes Next Give Clinical Labs New Diagnostic Tools?
The variety of new regions of the Y chromosome that the T2T team discovered bring into focus several areas of new genetic research. For instance, the “azoospermia factor region, a stretch of DNA containing several genes known to be involved in sperm production” was uncovered, and “with the newly completed sequence, the researchers studied the structure of a set of inverted repeats or palindromes in the azoospermia factor region,” SciTechDaily reported.
“This structure is very important because occasionally these palindromes can create loops of DNA. Sometimes, these loops accidentally get cut off and create deletions in the genome,” said Arang Rhie, PhD, a staff scientist at NHGRI and first author of the Nature study.
Missing regions would challenge the production of sperm, impacting fertility, so being able to finally see a complete sequence will help research in this area.
Scientists are only just beginning to recognize the value of this breakthrough to future genetic research and development. As genetic sequencing costs continue to drop, the T2T research findings could mean new treatment options for pathologists and diagnostic assays for clinical laboratories are just around the corner.
One of the world’s fastest growing medical laboratory companies in India is using digital pathology systems and AI to replace older diagnostic technologies
Artificial intelligence (AI) is gaining acceptance around the world and use of AI to analyze digital pathology images is expected to be a major disruptor to the profession of anatomic pathology. Internationally, several pathology companies already use AI-powered solutions to diagnose cancer.
One such example is Neuberg Diagnostics, a fast-growing clinical laboratory company in Chennai, India. Neuberg has been using AI to review digital pathology images for several years, according to Chairman and Managing Director GSK Velu, PhD, BPharm.
“We already use AI in our laboratories,” Velu said in an exclusive interview with Dark Daily. “Our main reference laboratories currently use digital pathology systems to support the pathologists and many of them are using AI with these digital pathology systems.
“AI and data analytics tools are being used in other departments too, such as in our wellness department where we use AI for predictive analytics,” he added. “We also use AI in our genomics division, and we are introducing AI into other divisions slowly and steadily.”
Neuberg operates 120 laboratories in an extensive network in India, South Africa, and the United Arab Emirates (UAE), and now in the US as well.
“Our idea is to enhance the access and affordability for next-generation techniques, meaning molecular diagnostics, genomics, pathology, digital pathology, proteomics, metabolomics, and all that. This is the spirit behind Neuberg Diagnostics,” said GSK Velu, PhD, BPharm (above), Chairman and Managing Director of Neuberg Diagnostics, in an exclusive interview with The Dark Report. Clinical laboratories that are considering investing in digital pathology technologies may want to follow its development at Neuberg’s Centre for Genomic Medicine in Raleigh, NC, which opened in May. (Photo copyright: Neuberg Diagnostics.)
Replacing Older Pathology Technologies
As has been happening at other anatomic pathology centers around the world, Neuberg has been using digital pathology systems to replace older technologies. “One of our largest labs is our Bangalore Reference Lab,” Velu said. “There, we do not use microscopes for histopathology, and that lab has used digital pathology for routine review of specimens for several years now.
“But because artificial intelligence is still emerging, we can’t rely on AI with all of our digital pathology systems,” he added. “Although, of course, AI is certainly an aid to everything we do with digital pathology.
“For a variety of reasons, the adaptation of artificial intelligence in anatomic pathology is not happening as effectively nor as fast as we would like,” he noted. “So, for now, we need to wait and watch a bit longer, either because adaptation by pathologists is slow, or because AI tools are still a bit of a worry for some pathologists.
Younger Pathologists Adapt Faster to Digital Pathology
One reason could be that conventional pathologists worry about relying completely on AI for any diagnosis, Velu noted. “I’m certain that the more recent generation of pathologists who are now in their 30s, and the new people coming into pathology, will start adapting more quickly to digital pathology and to AI faster than the older generation of pathologists have done.
“The younger pathologists have a greater appreciation for the potential of digital pathology, while the older pathologists don’t want to let go of conventional diagnosis methods,” he added.
“For example, we have not yet seen where pathologists are reviewing breast image scans,” he commented. “But, at the same time, AI has been well-accepted among radiologists who are reviewing breast mammography scans.”
In India and in other markets worldwide, radiologists have adapted AI tools for breast mammography scans to diagnose breast cancer, he noted. “But that’s not happening even among pathologists who are doing cancer screening,” he said.
Velu suggested that another reason for the slow adoption of AI tools in pathology is that these systems are relatively new to the market. “Maybe the AI tools that are used with digital pathology are not as reliable as we hoped they would be, or they are not fully robust at the moment,” he speculated. “That’s why I say it will take some time before the use of AI for diagnosis becomes more widespread among pathologists. So, for now, we must wait until digital pathology and AI tools work together more seamlessly.
Replacing Conventional Pathology Technologies and Methods
“When those two technologies—AI and digital pathology systems—are linked more closely, their use will take hold in a substantial way,” Velu predicted. “When that happens, they are likely to replace conventional pathology methods completely.
“Currently, we are in the early stages of a transformation,” he added. “In our labs, you can see that the transformation is ongoing. We are using digital pathology systems even in our smaller labs. Then, the staff in our smaller labs do the processing of slides to convert them to digital images and send them to our labs in the larger cities. There, the professional staff uses AI to review those digital images and issue reports based on those images.
“Using our digital pathology systems and AI in that way means that we can make that technology available even in smaller towns and villages that have access only to our smaller labs,” he commented.
Velu added that wider use of digital pathology systems could improve the quality of care that pathologists deliver to patients in a significant way, particularly in rural areas. “Here in India, we are not seeing a huge shortage of pathologists, except in rural areas and villages,” he explained. “In those places, we could run short of pathologists.
“That is the reason we are trying to adapt the use of telepathology more widely,” he noted. “To do that, we might have technicians and histologists who will do just processing of slides so that they can send the digital images to our pathologists located in larger cities. Then, those surgical pathologists will review the cases and send the reports out. That’s the model that we are trying to slowly follow here.”
As use of digital pathology images increased, many predicted that specimens would flow from the US to India. This would happen because of the belief that the lower cost of surgical pathology in India would successfully draw business away from pathology groups here in the United States.
However, Neuberg turned the tables on that belief when it announced the opening of its Neuberg Centre for Genomic Medicine (NCGM), a state-of-the-art esoteric and genetic testing laboratory in Raleigh, NC. The NCGM lab is CLIA-certified and Neuberg says it is ready to compete with labs in this country on their home turf.
These are reasons why pathologists and pathology practice administrators in the United States may want to watch how Neuberg Diagnostics continues to develop its use of digital pathology platforms and AI-powered digital image analysis tools throughout its international network of laboratories.
Using animal blood, the researchers hope to improve the accuracy of AI driven diagnostic technology
What does a cheetah, a tortoise, and a Humboldt penguin have
in common? They are zoo animals helping scientists at Saarland University in
Saarbrücken, Germany, find biomarkers that can help computer-assisted diagnoses
of diseases in humans at early stages. And they are not the only animals
lending a paw or claw.
In their initial research, the scientists used blood samples
that had been collected during routine examinations of 21 zoo animals between
2016 and 2018, said a news
release. The team of bioinformatics
and human genetics experts
worked with German zoos Saarbrücken and Neunkircher for the study. The project
progresses, and thus far, they’ve studied the blood of 40 zoo animals, the
release states.
This research work may eventually add useful biomarkers and
assays that clinical
laboratories can use to support physicians as they diagnose patients,
select appropriate therapies, and monitor the progress of their patients. As medical
laboratory scientists know, for many decades, the animal kingdom has been
the source of useful insights and biological materials that have been
incorporated into laboratory assays.
“Measuring the molecular blood profiles of animals has never
been done before this way,” said Andreas
Keller, PhD, Saarland University Bioinformatics Professor and Chair for
Clinical Bioinformatics, in the news release. The Saarland researchers published
their findings in Nucleic Acids
Research, an Oxford
Academic journal.
“Studies on sncRNAs [small non-coding RNAs] are often largely based on homology-based information, relying on genomic sequence similarity and excluding actual expression data. To obtain information on sncRNA expression (including miRNAs, snoRNAs, YRNAs and tRNAs), we performed low-input-volume next-generation sequencing of 500 pg of RNA from 21 animals at two German zoological gardens,” the article states.
Can Animals Improve the Accuracy of AI to Detect Disease
in Humans?
However, the researchers perceived an inability for AI and machine learning to
discern real biomarker patterns from those that just seemed to fit.
“The machine learning methods recognize the typical
patterns, for example for a lung tumor or Alzheimer’s disease. However, it is
difficult for artificial intelligence to learn which biomarker patterns are
real and which only seem to fit the respective clinical picture. This is where
the blood samples of the animals come into play,” Keller states in the news
release.
“If a biomarker is evolutionarily conserved, i.e. also
occurs in other species in similar form and function, it is much more likely
that it is a resilient biomarker,” Keller explained. “The new findings are now
being incorporated into our computer models and will help us to identify the
correct biomarkers even more precisely in the future.”
Andreas Keller, PhD (left), and zoo director Richard Francke (right), hold a pair of radiated tortoises that participated in the Saarland University study. (Photo copyright: Oliver Dietze/Saarland University.)
“Because blood can be obtained in a standardized manner and
miRNA expression patterns are technically very stable, it is easy to accurately
compare expression between different animal species. In particular, dried blood
spots or microsampling devices appear to be well suited as containers for
miRNAs,” the researchers wrote in Nucleic Acids Research.
Animal species that participated in the study include:
Additionally, human volunteers contributed blood specimens
for a total of 19 species studied. The scientists reported success in capturing
data from all of the species. They are integrating the information into their
computer models and have developed a public database of their
findings for future research.
“With our study, we provide a large collection of small RNA
NGS expression data of species that have not been analyzed before in great
detail. We created a comprehensive publicly available online resource for
researchers in the field to facilitate the assessment of evolutionarily
conserved small RNA sequences,” the researchers wrote in their paper.
Clinical Laboratory Research and Zoos: A Future
Partnership?
This novel involvement of zoo animals in research aimed at improving
the ability of AI driven diagnostics to isolate and identify human disease is
notable and worth watching. It is obviously pioneering work and needs much
additional research. At the same time, these findings give evidence that there
is useful information to be extracted from a wide range of unlikely sources—in
this case, zoo animals.
Also, the use of artificial intelligence to search for
useful patterns in the data is a notable part of what these researchers
discovered. It is also notable that this research is focused on sequencing DNA
and RNA of the animals involved with the goal of identifying sequences that are
common across several species, thus demonstrating the common, important
functions they serve.
In coming years, those clinical laboratories doing genetic
testing in support of patient care may be incorporating some of this research
group’s findings into their interpretation of certain gene sequences.
