Private Chinese Institute Wants to Make Whole Genome Sequencing Commonplace
Pathologists and clinical laboratory managers will be surprised to learn that China is poised to become the world leader in genome sequencing! That’s due to the ambitious goals of BGI, a privately-operated institute that plans to make genomics a topic that matters for ordinary people.
“The whole institute feels this huge responsibility,” said Wang Jun, Executive Director BGI, formerly Beijing Genomics Institute, in the March 2010 issue of the journal Nature.
Now headquartered in Shenzhen, BGI is gearing up to mass-produce cheap, quality genome sequences. This, in turn, may accelerate development of cost-effective, DNA-related diagnostic tests, clinical laboratory assays, and products for patient care.
To fulfill its mission, the institute has assembled an army of young bioinformaticians. Earlier this year, BGI aquired 128 new Illumina HiSeq 2000 genome sequencers. Collectively, these powerful, new gene sequencing systems mean that BGI now has the world’s largest, next-generation sequencing capacity. About 100 of the sequencing systems were installed in BGI’s Hong Kong lab to facilitate international collaborations.
Next-generation technology is able to sequence DNA at super-fast speeds. Outputs are now thousands of times greater than older sequencing technologies. The 128 Illumina sequencing systems would theoretically allow BGI to produce 10,000 whole human genome sequences per year. This capability is more than the entire U.S. sequencing output, noted David A. Wheeler, Ph.D., Director of Molecular Biology Computational Resources at Baylor College of Medicine in Houston. “It’s clear there is a new map of the genomics world,” he said, in the Nature article.
Both programs seek to achieve early diagnosis by detecting a range of disorders where an existing treatment can be given as early as possible
Two separate genetic sequencing projects—one in the United Kingdom and one in New York City—aim to perform whole-genome sequencing for clinical laboratory diagnostic purposes on 100,000 newborns each to identify up to 200 rare genetic disease that are treatable with early diagnosis and intervention.
Genomics England announced its Newborn Genomes Program in 2022 and plans to start signing up expectant parents for the genetic sequencing project later this year, an article in Science reported. Parents will be invited to participate in the $129 million pilot program through the UK’s National Health Service (NHS) with the goal of enrolling 100,000 newborns over the next two years.
In the US, the Guardian Study (Genomic Uniform-screening Against Rare Diseases In All Newborns) was launched last year in New York City. The program will run for four years and sequence the DNA of 100,000 newborns looking for 160 rare genetic diseases. “Parents can opt to add 100 neurodevelopmental disorders that can’t be cured, but for which speech and physical therapy could help,” Science noted.
More than 200 babies have already been enrolled in the Guardian study, and about 70% of those invited to participate have agreed to do so, according to GenomeWeb.
“I think expanding the number of diseases we look for could make a radical improvement in the way we diagnose and treat children with rare diseases,” said molecular geneticist Wendy Chung, MD, PhD, Director of the Clinical Genetics Program at New York Presbyterian Hospital/Columbia University Medical Center, in a press release. Clinical laboratories that perform newborn screenings may soon have new genomic screening tools for a larger number of rare genetic disorders. (Photo copyright: Columbia University.)
Giving Parents the Ability to Make Informed Decisions
In many countries, newborns are screened for several dozen genetic illnesses via biochemical tests using a drop of blood collected from the baby’s heel. Whole-genome sequencing could potentially detect more disorders and allow for earlier care and treatments to avoid permanent disability or death.
Parents enrolled in the US/UK genomics sequencing programs will receive results for as many as 200 genetic diseases that are known to be caused by genetic variants and which typically display symptoms before the age of five. All the illnesses are treatable with remedies ranging from a simple vitamin supplement to a bone marrow transplant.
“For the parents who may be offered whole genome sequencing for their babies as part of our pilot, they need to know which of these many conditions will be looked for, so that they can make an informed decision about whether or not to take part in the study,” said pediatrician and geneticist David Bick, MD, Principal Clinician for the Newborn Genomes Program, in a Genomics England press release.
Parents will not receive data regarding gene variants with unknown risks or variants that only cause disease in adulthood.
Detecting a Range of Genetic Disorders in Newborns
The UK’s Newborn Genomes Program expects to identify genetic disease in at least 500 newborns. Researchers involved in the project estimate that utilizing genetic sequencing in newborns could detect those diseases in up to 3,000 babies if used across the country.
“The primary goal of the program is to detect a range of disorders where we already have an intervention that could be given at the earliest possible point in life to reduce disability or potentially to avoid harm,” said Sir Mark Caulfield, MD, Director of the William Harvey Research Institute at Queen Mary University of London and Chief Scientist for Genomics England, in a Queen Mary University press release.
“It turns out that approximately one in 190 births (circa 10 babies born every day in the UK) has one of these problems, and if the intervention is employed, this could be life changing. The majority of these interventions are dietary shifts or vitamin supplements, and only 8% are expensive treatments, for example, gene therapies or transplantation,” Caulfield noted. “The children may not be cured, but the interventions may reduce disability or even allow a normal life, so getting these life-changing opportunities to children at the earliest point is so important.”
The US initiative is using genomic sequencing to screen for 250 medical conditions that are not currently detectable in newborn screenings in New York. Like the UK program, these disorders are treatable and symptomatic before the age of five. The goal is to diagnose these illnesses earlier to allow for early treatment and better health outcomes.
“I think expanding the number of diseases we look for could make a radical improvement in the way we diagnose and treat children with rare diseases”, said Chung in a Columbia University press release. “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.
“I think genomic screening will also make sure we leave no baby behind. It will provide equitable access to a diagnosis,” Chung added. “We want to address health disparities, which we’ve seen happen after screening for SCID (severe combined immunodeficiency disorders) was added to state newborn screening panels. When every newborn is screened, the family’s socioeconomic status is irrelevant.”
Saving Children from Lifelong Disease
The US and UK genomics sequencing programs may have considerable influence on encouraging more newborn screening all over the world. Technological advancements in recent years have dramatically reduced genomic sequencing costs.
Additionally, sequences can be done faster and more accurately, and the technology is enabling complex analysis of data in ways that expands the information contained in the genome. This could lead to life-saving breakthroughs in treatment for many rare genetic disorders.
These developments may also encourage more clinical laboratories within the United States to consider offering a genome sequencing service for newborn screening. With hundreds of diseases now detectable through genetic technology, screening a newborn’s genome for mutations could provide more accurate and faster diagnosis of illnesses and potentially help more children avoid serious diseases.
Declining health of UK’s population also affecting performance of the country’s national health service, report notes
England’s National Health Service (NHS) is “in serious trouble” due to long waiting times, outdated technology, misallocated resources, and numerous other problems, with dire consequences for the country’s populace. That’s according to a new report by NHS surgeon and former Health Minister Lord Ara Darzi, OM KBE FRS FMedSci HonFREng, who was tasked by the United Kingdom’s new Labor government to investigate the ailing healthcare system. His report may contain lessons for US healthcare—including clinical laboratories—as well.
“Although I have worked in the NHS for more than 30 years, I have been shocked by what I have found during this investigation—not just in the health service but in the state of the nation’s health,” Darzi stated in a UK government press release. “We want to deliver high quality care for all but far too many people are waiting for too long and in too many clinical areas, quality of care has gone backwards.”
Many of the problems he identified relate to wait times.
“From access to GPs (general practitioners) and to community and mental health services, on to accident and emergency, and then to waits not just for more routine surgery and treatment but for cancer and cardiac services, waiting time targets are being missed,” he wrote in his report.
For example, “as of June 2024, more than one million people were waiting for community services, including more than 50,000 people who had been waiting for over a year, 80% of whom are children and young people,” he wrote.
Accident and emergency care (A/E) “is in an awful state,” the report noted, “with A/E queues more than doubling from an average of just under 40 people on a typical evening in April 2009 to over 100 in April 2024. One in 10 patients are now waiting for 12 hours or more.”
“In the last 15 years, the NHS was hit by three shocks—austerity and starvation of investment, confusion caused by top-down reorganization, and then the pandemic which came with resilience at an all-time low. Two out of three of those shocks were choices made in Westminster,” said NHS surgeon and former Health Minister Lord Ara Darzi in a government press release. “It took more than a decade for the NHS to fall into disrepair so it’s going to take time to fix it. But we in the NHS have turned things around before, and I’m confident we will do it again.” (Photo copyright: Health Data Research UK.)
Delays in Other Critical Tests
Genetic test results are lagging as well. “In 2024, more than 35,000 genomic tests are being completed each month but only around 60% on time,” Darzi wrote.
He also noted that “only around 5% of eligible patients with brain cancer are able to access whole genome sequencing (WGS), which is important for treatment selection.” Just two-thirds (65.8%) get their first treatment within 62 days, and more than 30% wait more than 31 days for radical radiotherapy, according to the report.
Overall, “the UK has appreciably higher cancer mortality rates than other countries, with no progress whatsoever made in diagnosing cancer at stage one and two between 2013 and 2021,” he wrote.
Patients have also experienced delays in access to cardiovascular treatment. For example, in 2013-2014, high-risk heart attack patients waited an average of 114 minutes for intervention to unblock an artery, Darzi noted in his report. However, in 2022-2023, the average time was 146 minutes, a 28% increase.
“For the most part, once people are in the system, they receive high quality care,” he wrote. “But there are some important areas of concerns, such as maternity care, where there have been a succession of scandals and inquiries.”
Key Factors Leading to Delays
Darzi pointed to four key factors that have led to the problems.
Lack of funding. “The 2010s was the most austere decade since the NHS was founded, with spending growing at around 1% in real terms,” Darzi wrote, compared with a long-term average of 3.4%.
One result was that administrators took funds from the capital budget to cover day-to-day needs, leading to “crumbling buildings that hit productivity,” he noted.
“The backlog maintenance bill now stands at more than £11.6 billion and a lack of capital means that there are too many outdated scanners, too little automation, and parts of the NHS are yet to enter the digital era,” he wrote.
The COVID-19 pandemic. Given the preceding “decade of austerity,” NHS had fewer resources to deal with the crisis than most other high-income health systems, he wrote. As a result, NHS “delayed, cancelled, or postponed far more routine care during the pandemic than any comparable health system.” This led to “a bigger backlog than other health systems.”
Lack of patient and staff engagement. Patient satisfaction “has declined and the number of complaints has increased, while patients are less empowered to make choices about their care,” he wrote. In addition, “too many staff have become disengaged, and there are distressingly high-levels of sickness absence—as much as one working month a year for each nurse and each midwife working in the NHS.”
Management structures and systems. Darzi laid considerable blame on the UK’s Health and Social Care Act of 2012, which led to what he described as “a costly and distracting process of almost constant reorganization of the ‘headquarters’ and ‘regulatory’ functions of the NHS.”
One consequence, he wrote, is that too many clinicians have been deployed in hospitals instead of community-based care, despite years of promises by successive governments to put more emphasis on the latter.
National Health in Decline
Along with issues within the NHS, “the health of the nation has deteriorated and that impacts its performance,” Darzi wrote. “There has been a surge in multiple long-term conditions, and, particularly among children and young people, in mental health needs. Fewer children are getting the immunizations they need to protect their health, and fewer adults are participating in some of the key screening programs, such as for breast cancer.”
Darzi’s investigation included frontline visits to NHS facilities as well as focus groups with NHS staff and patients, the press release states. He also consulted an expert reference group consisting of more than 70 organizations and examined analyses from NHS England, the UK’s Department of Health and Social Care, and external groups.
It is interesting that there is no mention of anatomic pathology and medical laboratory testing services in Lord Darzi’s report. As reported in recent years by new outlets in the United Kingdom, delays in cancer diagnoses—often as long as six months—were severe enough that, in 2018, the NHS announced funding for a program to create a national digital pathology network to improve productivity of pathologists and shorten wait times for the results of cancer tests.
Though not biomarkers per se, these scores for certain genetic traits may someday be used by clinical laboratories to identify individuals’ risk for specific diseases
Can polygenic risk scores (a number that denotes a person’s genetic predisposition for certain traits) do a better job at predicting the likelihood of developing specific diseases, perhaps even before the onset of symptoms? Researchers at the Broad Institute of MIT and Harvard (Broad Institute) believe so, and their study could have implications for clinical laboratories nationwide.
In cooperation with medical centers across the US, the scientists “optimized 10 polygenic scores for use in clinical research as part of a study on how to implement genetic risk prediction for patients,” according to a Broad Institute news release.
The research team “selected, optimized, and validated the tests for 10 common diseases [selected from a total of 23 conditions], including heart disease, breast cancer, and type 2 diabetes. They also calibrated the tests for use in people with non-European ancestries,” the news release notes.
As these markers for genetic risk become better understood they may work their way into clinical practice. This could mean clinical laboratories will have a role in sequencing patients’ DNA to provide physicians with information about the probability of a patient’s elevated genetic risk for certain conditions.
However, the effectiveness of polygenic risk scores has faced challenges among diverse populations, according to the news release, which also noted a need to appropriately guide clinicians in use of the scores.
“With this work, we’ve taken the first steps toward showing the potential strength and power of these scores across a diverse population,” said Niall Lennon, PhD (above), Chief Scientific Officer of Broad Clinical Labs. “We hope in the future this kind of information can be used in preventive medicine to help people take actions that lower their risk of disease.” Clinical laboratories may eventually be tasked with performing DNA sequencing to determine potential genetic risk for certain diseases. (Photo copyright: Broad Institute.)
Polygenic Scores Need to Reflect Diversity
“There have been a lot of ongoing conversations and debates about polygenic risk scores and their utility and applicability in the clinical setting,” said Niall Lennon, PhD, Chair and Chief Scientific Officer of Broad Clinical Labs and first author of the study, in the news release. However, he added, “It was important that we weren’t giving people results that they couldn’t do anything about.”
In the paper, Lennon and colleagues explained polygenic risk scores “aggregate the effects of many genetic risk variants” to identify a person’s genetic predisposition for a certain disease or phenotype.
“But their development and application to clinical care, particularly among ancestrally diverse individuals, present substantial challenges,” they noted. “Clinical use of polygenic risk scores may ultimately prevent disease or enable its detection at earlier, more treatable stages.”
The scientists set a research goal to “optimize polygenic risk scores for a diversity of people.”
While performing the polygenic risk score testing on participants, Broad Clinical Labs focused on 10 conditions—including cardiometabolic diseases and cancer—selected by the research team based on “polygenic risk score performance, medical actionability, and clinical utility,” the Nature Medicine paper explained.
For each condition, the researchers:
Identified “exact spots in the genome that they would analyze to calculate the risk score.”
Used information from the NIH’s All of Us Research Program to “create a model to calibrate a person’s polygenic risk score according to that individual’s genetic ancestry.”
The All of Us program, which aims to collect health information from one million US residents, has three times more people of non-European ancestry than other data sources developing genetic risk scores, HealthDay News reported.
20% of Study Participants Showed High Risk for Disease
To complete their studies, Broad Institute researchers processed a diverse group of eMERGE participants to determine their clinical polygenic risk scores for each of the 10 diseases between July 2022 and August 2023.
Listed below are all conditions studied, as well as the number of participants involved in each study and the number of people with scores indicating high risk of the disease, according to their published paper:
Over 500 people (about 20%) of the 2,500 participants, had high risk for at least one of the 10 targeted diseases, the study found.
Participants in the study self-reported their race/ancestry as follows, according to the paper:
White: 32.8%
Black: 32.8%
Hispanic: 25.4%
Asian: 5%
American Indian: 1.5%
Middle Eastern: 0.9%
No selection: 0.8%
“We can’t fix all biases in the risk scores, but we can make sure that if a person is in a high-risk group for a disease, they’ll get identified as high risk regardless of what their genetic ancestry is,” Lennon said.
Further Studies, Scoring Implications
With 10 tests in hand, Broad Clinical Labs plans to calculate risk scores for all 25,000 people in the eMERGE network. The researchers also aim to conduct follow-up studies to discover what role polygenic risk scores may play in patients’ overall healthcare.
“Ultimately, the network wants to know what it means for a person to receive information that says they’re at high risk for one of these diseases,” Lennon said.
The researchers’ findings about disease risk are likely also relevant to healthcare systems, which want care teams to make earlier, pre-symptomatic diagnosis to keep patients healthy.
Clinical laboratory leaders may want to follow Broad Clinical Labs’ studies as they perform the 10 genetic tests and capture information about what participants may be willing to do—based on risk scores—to lower their risk for deadly diseases.
Study findings could lead to new clinical laboratory diagnostics that give pathologists a more detailed understanding about certain types of cancer
New studies proving artificial intelligence (AI) can be used effectively in clinical laboratory diagnostics and personalized healthcare continue to emerge. Scientists in the UK recently trained an AI model using machine learning and deep learning to enable earlier, more accurate detection of 13 different types of cancer.
DNA stores genetic information in sequences of four nucleotide bases: A (adenine), T (thymine), G (guanine) and C (cytosine). These bases can be modified through DNA methylation. There are millions of DNA methylation markers in every single cell, and they change in the early stages of cancer development.
One common characteristic of many cancers is an epigenetic phenomenon called aberrant DNA methylation. Modifications in DNA can influence gene expression and are observable in cancer cells. A methylation profile can differentiate tumor types and subtypes and changes in the process often come before malignancy appears. This renders methylation very useful in catching cancers while in the early stages.
However, deciphering slight changes in methylation patterns can be extremely difficult. According to the scientists, “identifying the specific DNA methylation signatures indicative of different cancer types is akin to searching for a needle in a haystack.”
Nevertheless, the researchers believe identifying these changes could become a useful biomarker for early detection of cancers, which is why they built their AI models.
“Computational methods such as this model, through better training on more varied data and rigorous testing in the clinic, will eventually provide AI models that can help doctors with early detection and screening of cancers,” said Shamith Samarajiwa, PhD (above), Senior Lecturer and Group Leader, Computational Biology and Genomic Data Science, Imperial College London, in a news release. “This will provide better patient outcomes.” With additional research, clinical laboratories and pathologists may soon have new cancer diagnostics based on these AI models. (Photo copyright: University of Cambridge.)
The researchers then used a combination of machine learning and deep learning techniques to train an AI algorithm to examine DNA methylation patterns of the collected data. The algorithm identified and differentiated specific cancer types, including breast, liver, lung and prostate, from non-cancerous tissue with a 98.2% accuracy rate. The team evaluated their AI model by comparing the results to independent research.
In their Biology Methods and Protocols paper, the authors noted that their model does require further training and testing and stressed that “the important aspect of this study was the use of an explainable and interpretable core AI model.” They also claim their model could help medical professionals understand “the underlying mechanisms that contribute to the development of cancer.”
Using AI to Lower Cancer Rates Worldwide
According to the Centers for Disease Control and Prevention (CDC), cancer ranks as the second leading cause of death in the United States with 608,371 deaths reported in 2022. The leading cause of death in the US is heart disease with 702,880 deaths reported in the same year.
Globally cancer diagnoses and death rates are even more alarming. World Health Organization (WHO) data shows an estimated 20 million new cancer cases worldwide in 2022, with 9.7 million persons perishing from various cancers that year.
The UK researchers are hopeful their new AI model will help lower those numbers. They state in their paper that “most cancers are treatable and curable if detected early enough.”
More research and studies are needed to confirm the results of this study, but it appears to be a very promising line of exploration and development of using AI to detect, identify, and diagnose cancer earlier. This type of probing could provide pathologists with improved tools for determining the presence of cancer and lead to better patient outcomes.
