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.
Goal is to demonstrate how whole human genome sequencing of newborns can deliver important diagnostic findings associated with 250 genetic conditions
Clinical laboratory testing and genetics are moving closer to the delivery room than ever before. In the largest study of its kind in North America, genomic scientists plan to supplement traditional screening for inherited diseases—traditionally performed on a blood sample taken shortly after birth—with whole genome sequencing (WGS) on 100,000 newborns in New York City during their first five years of life, LifeSciencesIntelligence reported.
Conducted by genetic scientists at NewYork-Presbyterian (NYP) and Columbia University, in collaboration with genetic company GeneDx, a wholly-owned subsidiary of health intelligence company Sema4 (NASDAQ:SMFR), the genetic research study, called GUARDIAN (Genomic Uniform-screening Against Rare Diseases In All Newborns), will screen newborn babies for 250 rare diseases that are generally not tested for.
The GUARDIAN program will “drive earlier diagnosis and treatment to improve the health of the babies who participate, generate evidence to support the expansion of newborn screening through genomic sequencing, and characterize the prevalence and natural history of rare genetic conditions,” according to a Sema4 news release.
“The appetite for this is growing. The awareness of this is growing. We all see it as inevitable,” medical geneticist Robert Green, MD, at Brigham and Women’s Hospital and Harvard Medical School told USA Today. “We are grossly underutilizing the life-saving benefits of genetics and we have to get past that.” Clinical laboratory leaders understand the value of early detection of disease and subsequent early treatment. (Photo copyright: Harvard Medical School.)
Improving Health of Babies Through Early Detection of Disease
GUARDIAN aims to use WGS to identify conditions at birth that can affect long-term health and subsequently enhance treatment options and possibly prevent disability or death.
The 250 different diseases GUARDIAN will be screening for typically strike young children. They are mostly rare conditions that:
have an onset before five years of age,
have a greater than 90% probability of the condition developing based on the genetic result,
have effective approaches and treatments that are already available, and/or
have a well-established natural history of the condition.
“We’re entering the therapeutic era and leaving the diagnostic era,” Paul Kruszka, MD, Chief Medical Officer at GeneDx told USA Today. “This potentially has the opportunity to change the way we practice medicine, especially in rare disease.”
Some Parents Reluctant to Agree to Genetic Testing
Green and his research team first began analyzing the genetic sequences of newborns back in 2013. They believe the costs of performing infant WGS is worthwhile because it can improve lives. However, Green also recognizes that some parents are reluctant to agree to this type of genetic testing due to concerns regarding privacy and the fear of discovering their baby may have an illness.
“You’ve gone through all this pregnancy and you’re sitting there with a healthy baby (and I’m) offering you the opportunity to find out something that’s devastating and terrifying,” he told USA Today. “How fun is that?”
Green continued. “We can respect people who don’t want to know, but also respect people who do want to know. Some families will say ‘I treasure the precious ignorance.’ Others will say ‘If I could have known, I would have poured my heart and soul into clinical trials or spent more time with the child when she was healthy.’”
WGS Screening Identifies Undiagnosed Illnesses in Newborn’s Family
The scientists also found that performing WGS in newborns can detect diseases in the infants as well as unknown illnesses in the families of those babies. According to Kruszka, many parents often seek a diagnosis for a rare disease present in their children for several years. Since many common diseases develop as a result of certain combinations of genes, if illnesses are diagnosed at birth, it could extradite the treatment process, prevent complications, and provide better health outcomes for patients.
“We are relentlessly focused on accelerating the adoption and use of genomic information to impact the lives of as many people as possible, particularly newborns and children,” said Katherine Stueland, President and CEO, Sema4, in the Sema4 news release. “As the first commercial laboratory to launch a rapid whole genome sequencing offering, to address broad unmet needs for early diagnosis, participation in this study is an important step forward for healthcare and in delivering on our goal to sequence once, analyze forever.”
The study is open to all babies in New York City who are born in a health system that participates in the GUARDIAN program, regardless of their race, income, or health insurance coverage.
“The results from this study will help us understand the true impact sequencing at birth can have on newborns and their families in comparison to the current standard of care, particularly as we’ll evaluate clinical outcomes in addition to the psychosocial effect on families,” said Kruszka in the Sema4 news release.
Anything that improves the health of newborn babies is a good thing. Regardless of the cost, if DNA analysis can give newborns and their families a better chance at detecting inherited diseases early while clinical laboratory treatment could make a difference, it is worth pursuing.
Balwani’s lawyers opted not to have their client testify in his own defense and called only two witnesses, while Holmes’ defense team offered jurors the opportunity to hear her testimony
Elizabeth Holmes and Ramesh “Sunny” Balwani dreamed of revolutionizing the clinical laboratory blood-testing industry with their now defunct Theranos Edison device, which they claimed could perform multiple tests with a single finger prick of blood. Instead, they became the rare Silicon Valley executives to be convicted of fraud.
On July 7, ex-COO/President Balwani was convicted on all 12 counts of wire fraud and conspiracy charges in his federal fraud trial. Holmes, Theranos’ founder/CEO and former romantic partner to Balwani, avoided convictions six months ago in January on seven of the 11 counts she faced for her role in exaggerating the accuracy and reliability of the company’s Edison blood-testing device and providing false financial claims to investors.
“Once again, a jury has determined that the fraud at Theranos reached the level of criminal conspiracy,” said FBI Special Agent in Charge Sean Ragan in a press release posted on Twitter following the verdict. “The FBI has spent years investigating this investment fraud scheme with our partners at USPIS and the FDA Office of Criminal Investigations. Lies, deceit, and criminal actions cannot replace innovation and success.”
Ramesh “Sunny” Balwani (above center), former COO/President of Theranos, is shown leaving the federal courthouse in San Jose, Calif., on July 7 after he was found guilty on all 12 counts of fraud, a verdict more severe than ex-CEO and Theranos founder Elizabeth Holmes received in January for similar charges. Clinical laboratory directors and medical laboratory scientists have been closely monitoring both trails. (Photo copyright: Jim Wilson/The New York Times.)
Balwani’s Age and Experience May Have Worked Against Him
Michael Weinstein, JD, a former Justice Department prosecutor who is the Chair of White-collar Litigation at Cole Schotz, told The New York Times that Balwani’s age and his trial date—three months after Holmes’ conviction—worked against him. Balwani, 57, could not present himself as a young and inexperienced tech executive easily manipulated by those around him, as Holmes, 38, had attempted to do.
“Holmes could come off as a bit naïve, and [her defense team] tried to sell that,” Weinstein said of the former Stanford University dropout who founded Theranos in 2003 when she was 19.
In Holmes’ case the verdict was mixed, with jurors acquitting her of the patient fraud counts but unable to reach a decision on some of the investor fraud counts, Bloomberg reported.
Mr. Balwani, however, “came off as more of an experienced technology executive,” Weinstein added.
Weinstein pointed out that because the government’s case against Balwani mirrored its case against Holmes, prosecutors had time to refine their strategy before making a second appearance inside US District Court Judge Edward Davila’s San Jose courtroom.
“The streamlined presentation, the streamlined evidence, the streamlined narrative—all was beneficial for the government in the end,” he said.
Ever since opening arguments in March, Balwani’s legal team portrayed him to the jurors as a loyal partner who believed in Theranos’ technology and “put his money where his mouth is,” the Guardian noted.
Prosecutors, however, made the case that Balwani had a hands-on role in running the lab and was the source of Theranos’ overinflated financial projections.
Balwani invested about $15 million in the startup between 2009 and 2011 and never cashed in when his stake grew to $500 million. That money evaporated when Theranos collapsed.
In all, 24 witnesses testified against Balwani. He was ultimately convicted of all 12 counts he faced:
Two counts of conspiring with Holmes,
Six counts of defrauding investors, and
Four counts of patient fraud.
Major Differences in Trial Testimony
The Balwani trial made headlines due to COVID-19 pandemic related delays, but otherwise did not produce the news-generating moments that punctuated Holmes’ nearly four-month-long court appearance. Thirty-two witnesses appeared at the Holmes trial, including Secretary of Defense James Mattis, according to CNN.
Another significant difference in the two trials was that Holmes testified in her own defense. Holmes spent nearly 24 hours on the stand, CNN Business noted at that time, during which she cast the blame for Theranos’ failings on those around her, including Balwani.
ABC NewsRebecca Jarvis, host and creator of the podcast “The Dropout,” believes Balwani’s decision not to testify worked against him.
“[The abuse claims] did not come up at his trial, but during [Holmes’] seven days of testimony, they were a big portion of what she talked about,” Jarvis said in an ABC News “Start Here” podcast. “The biggest difference is that he didn’t take the stand to say, ‘I didn’t do this,’ or … raise his own objections to the claims against him.
“You think about a jury who is supposed to know nothing about any of [the defendant’s] backstory, and they’re shown these things like … case pictures of [Holmes] so much younger than [Balwani], supposedly having to rely on him for his expertise,” Jarvis added.
“You can imagine where the jury may have found that presentation more sympathetic than Sunny Balwani who had experience,” she said.
Text May Have Been Balwani’s Undoing
Balwani’s defense team called only two witnesses:
A naturopathic physician who used Theranos’ blood-testing lab, and
A technical consultant who Balwani’s legal team hired to assess the accessibility of patient data in Theranos’ Laboratory Information System (LIS), which the defense argued could have provided evidence of the accuracy of Theranos’ test results.
“This verdict also signals the jurors did not buy Balwani’s highly speculative argument that the database Theranos lost in 2018 would have proven his innocence,” Park said.
“We are obviously disappointed with the verdicts,” he said. “We plan to study and consider all of Mr. Balwani’s options including an appeal.”
Following the verdicts, Judge Davila raised Balwani’s bail to $750,000 and set a Nov. 15 sentencing date. Holmes is scheduled to be sentenced Sept. 26.
Balwani’s own words may have been his final undoing. During closing arguments, prosecutors again showed jurors a text message Balwani sent to Holmes in 2015, The New York Times reported.
“I am responsible for everything at Theranos,” he wrote. “All have been my decisions too.”
Clinical laboratory directors and medical laboratory scientists will no doubt continue to monitor the fallout from these two extraordinary federal fraud trials. There’s still much to learn about CLIA-laboratory director responsibility and how the government plans to prevent future lab testing fraud from taking place.
