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February 3, 2025

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Stephen Kingsmore’s Quest to Transform Newborn Screening

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By Wendy Diller

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Overview

Stephen Kingsmore, MB, ChB, DSc, is enhancing whole genomic sequencing with AI to increase precision and accuracy of newborn screenings.

Making WGS Screenings Feasible for Babies Ultra-rare Genetic Diseases

Stephen Kingsmore, MB, ChB, DSc, a geneticist, is pioneering the rapid diagnosis and treatment of young children with rare genetic diseases. Previous to his work, no general method existed to translate results of whole genome testing into treatment guidance in a way that most physicians could put into practice.

As president and CEO of the Rady Children’s Institute for Genomic Medicine in San Diego, Kingsmore has spent decades building a scientifically rigorous infrastructure for running whole genomic sequencing diagnostic testing and delivering clinically actionable results as fast as possible to physicians and families.

Scientists have identified roughly 10,000 ultra-rare genetic diseases, but Kingsmore estimates that today only about 2,000 of these benefit from therapeutic interventions based on test results.

Currently, these diseases are diagnosed only after a child falls ill and undergoes a lengthy testing odyssey that may or may not result in treatment. However, critically ill children often do not have the luxury of time, which is increasingly urgent as drug companies develop groundbreaking medicines that require early interventions for some rare diseases.

In his quest for speed, Kingsmore has become a leading advocate of universal whole genome sequencing (WGS) for all newborns. His aim is to identify babies at birth who are at risk of hundreds and potentially thousands of ultra-rare diseases, then begin treating them within weeks. Doing this requires developing advanced automated technologies, designing new kinds of clinical trials, and forming global collaborations and educational partnerships. Because the babies being tested have healthy phenotypes and do not manifest signs of disease, even if they carry pathogenic mutations, testing performance has to be extremely rapid, sensitive and accurate.

In the diagnostic world, the Institute has already racked up impressive achievements. Kingsmore and his group are credited with having the fastest genetic diagnosis of a child with a rare disease. In 2016, that performance --26 hours from sample collection to diagnosis—made it into the Guinness Book of World Records. In 2018, the group broke its own record by performing rapid WGS in 19 hours from collection to results.

Thanks to this group, the entire WGS process from prescribing and executing to interpretating results and informing physicians in the Rady neonatal intensive care unit (NICU) or pediatric intensive care units can appear to be seamless. Kingsmore and his group have published prolifically on their work in top-tier journals, including Nature and the New England Journal of Medicine.

But universal WGS at the scale Kingsmore envisions is another challenge altogether. Medical genome sequencing currently is much too expensive to run on every newborn, which in the US alone tallies about 3.7 million babies each year.

Also, the false positive rate of WGS screening of apparently healthy babies is unacceptably high for population use. That is, WGS produces too many genome findings that inaccurately identify a newborn as at risk of a genetic disease, with the potential to create unnecessary concerns and unproductive clinical follow ups.

To address these barriers, Kingsmore proposes a highly automated, AI-driven WGS process that requires limited human intervention and results in treatment decisions based on carefully researched mathematical modeling.

Given that the applications are for ultra-rare diseases, proving the value of his proposition requires running extremely large, complex clinical trials. Kingsmore has spent considerable time figuring out the best strategies for producing that evidence.

“This has never been done before,” he said, “When we diagnose children using rapid whole genome sequencing, we use advanced technologies, but in the screening mode, we need to be much more demanding, more precise, and more accurate.”

The BeginNGS Approach to Disrupting Newborn Screening

In 2021, Kingsmore began an innovative series of studies called BeginNGS to study the feasibility and clinical utility of expanded newborn screening for ultra-rare genetic diseases. Other groups are conducting newborn screening studies, both in the US and abroad, but Rady’s is the most rigorous, Kingsmore said.

Many of the strategies Rady researchers use to carry out BeginNGS are designed from scratch. This includes combining WGS with a novel database called GTRx (Genome-to-Treatment), which provides information on relevant treatment options for specific ultra-rare genetic diseases. GTRx was developed by Rady researchers and industry collaborators to provide practical guidance for physicians in ways they can understand, given that most providers never see patients with these disorders.

The first two phases of BeginNGS were based on retrospective studies to confirm the clinical trial design, performance characteristics, and feasibility of scaling Rady’s approach. First, BeginNGS, Rady researchers settled on looking for 388 rare diseases with clinically actionable utility, studying 2,208 critically ill newborns with suspected genetic disorders and the UK Biobank database.

Then, using Rady’s rapid WGS, they determined that the technology had a specificity of 99.6 percent and sensitivity of 88.8 percent, which was far better than their expectations and slightly higher than rapid WGS when used for diagnostic applications. They published their results in 2023 in the American Journal of Human Genetics.

In July 2024, a second phase of BeginNGS trials finished. These used a refined, more powerful screening technology for 412 severe childhood genetic disorders (SCGD) and 53,855 variants. The American Journal of Human Genetics published results of these studies, one retrospective and one a prospective pilot, based on this latest technology in December 2024.

These studies, for the first time, demonstrated the ability of the BeginNGS approach to address the high rates of infant hospitalization and mortality in the US. Their success has given the Rady scientists confidence to proceed to a much larger prospective multi-center clinical trial, which is now underway, which aims to gradually enroll 100,000 infants during the next few years. Preliminary results should be available when the study has tested 10,000 infants, likely in early 2026.

BeginNGS Has 100 Percent True Positives, Enabling Scaling

With the studies’ December 2024 publication, the technology’s performance characteristics demonstrated its readiness for mass screening, due to its accuracy, affordability and speed of turnaround.

“We now have a platform that is ready for us to scale 10,000 or 100,000 or more children, which was not the case previously,” Kingsmore said.

The platform, as he intended, is highly automated, requires minimal human intervention to operate, and has a very low false-positive rate, all exacting features that are important for screening on such a massive scale. It is “the only platform available that has that capacity,” Kingsmore said.

To achieve this performance, the researchers used a mathematical concept called purifying hypersensitivity, a version of ‘extreme’ natural selection. They also built mathematical models of many of the disease variants to understand what their testing needed to look for. And they deployed a computational approach called query federation, which facilitates scaling because it allows genome data to be analyzed remotely, without actually sharing or moving it, thereby making the data more accessible to broader audiences.

Using the purifying hypersensitivity approach, blood samples of more than 3,000 infants in a NICU suspected of having genetic diseases were compared to those of more than 600,000 healthy middle-aged and elderly adults, on the assumption that the latter would not have reached adulthood if they had DNA variants that cause serious childhood diseases. The adult datasets came from the UK Biobank and Mexico City Prospective Study.

Investigators found that 2 percent of the healthy adults tested positive for genetic mutations related to diseases in the study, a very low rate, and those adults would have exhibited very mild forms of the disease, if at all. Nearly 8 percent of the newborns tested positive.

They found no false positives, confirming the rigor of the hypersensitivity design. One in 14 of the infants tested would have benefited from BeginNGS. Specifically, the baby would have received a diagnosis and treatment 121 days earlier than the current gold standard, which is to test after symptom onset, according to the Rady researchers’ calculations. In addition, testing revealed that BeginNGS would have benefited one in 13 babies who died in infancy.

The second study evaluated whether BeginNGS was ready for broader expansion. In a pilot trial, 120 babies in the NICU at Rady Children’s Hospital received the BeginNGS screening. Results were compared with traditional, federally mandated newborn screening and rapid diagnostic genome sequencing, which evaluated about 10,000 genetic diseases.

This trial found that nearly 30 percent of NICU babies who, at birth weren’t considered to need genome sequencing actually had genetic diseases, a rate similar to the diagnostic rate among babies who had been suspected of having genetic diseases, said Kingsmore.

Now that work is done, the next step is to expand the test menu to find more ultra-rare variants, bringing the number of diseases the WGS could detect during screening to 2,000. While still only a fraction of the roughly 10,000 known ultra-rare diseases, these are most likely to be clinically actionable.

It’s not clear what an acceptable cost would be for a universal newborn screening test of that magnitude, but as a reference, California currently pays $212 for an 89-test screening panel that it mandates for every infant born in the state. Still, Kingsmore said, “The dirty secret is that cost effectiveness has not been rigorously studied for these tests, so we do not know the societal cost.”

As the number of genetic diseases considered "treatable" is rapidly expanding due to novel cell and gene therapies and other new medicines, gene and variant lists for genetic newborn screening will also need to be frequently adjusted. It is unclear, though, how infants with a pathogenic mutation who do not show disease symptoms yet should be treated, Kingsmore added.

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