NEW YORK – BeginNGS, the whole-genome sequencing-based newborn screening program led by Rady Children's Institute for Genomic Medicine (RCIGM), is expanding to multiple hospitals in the US and potentially beyond.
Currently in its third phase, BeginNGS has enrolled San Diego Perinatal Center, Regional One Health in Tennessee, and University of Colorado Anschutz Medical Campus for its clinical trial, according to a spokesperson from RCIGM. The project is also looking to expand to Africa, though the institute did not share more details at this point.
The expansion of BeginNGS resonates with the increasing interest in WGS-based newborn screening in the US and beyond. The National Institutes of Health, for instance, last week launched a Newborn Screening by Whole Genome Sequencing (NBSxWGS) initiative, which will award up to $14.4 million in funding to evaluate the feasibility of WGS as a first-tier assay for newborn screening.
An RCIGM spokesperson said the institute is currently “reviewing the details of the NIH announcement to determine next steps but has not made any decisions yet” about applying for the funding.
Meredith Wright, technical innovation program manager at RCIGM, said the third phase of BeginNGS focuses on scaling. “The goal of phase three is to bring more diverse adult reference populations and pediatric populations into the federated query model, so that we can ensure that the test is performing equitably across genetic ancestries.”
According to Wright, the overall goal of the third phase is to “compare utility, acceptability, feasibility, and cost effectiveness” of WGS-based newborn screening with that of the traditional biochemical approach, “providing key foundational evidence for widespread adoption” of the technology. The project plans to enroll about 10,000 neonates by next year, she noted, and hopefully reach 100,000 over a five-year period.
Similar to the second phaseof the project, phase three also contains two arms: one retrospective, which focuses on optimizing the BeginNGS assay to improve its performance, and one prospective, which aims to ensure the test can be implemented in a scalable and equitable way, Wright said.
The retrospective study expands on that from phase two, which utilized existing WGS diagnostic sequencing data from RCIGM and population genomics data from the UK Biobank and the Mexico City Prospective Study as controls.
As more diagnostic WGS data and additional population sequencing datasets are made available, the BeginNGS test is including new genes, conditions, and variants across populations that represent a broader ancestral background, Wright noted.
For the prospective arm, parents can provide informed consent to enroll their newborns in three ways: prenatally, postnatally in newborn nurseries or NICUs, or during well baby visits to pediatricians. Neonates less than 28 days old can be enrolled if their parents have identified a primary care provider or group.
“Phase three is the first time we are approaching babies that do not have any known genetic issue,” said Jenny Mehlow, a spokesperson for RCIGM. “We are talking to parents who have no inclination that there may be anything wrong with their child.”
The rollout of the new phase is underpinned by the promising findings observed in phase two, Wright said, which were described in two separate papers published concurrently in the American Journal of Human Genetics last December.
The first paper demonstrated that using samples from 7,342 children, parents, or siblings who received rapid diagnostic WGS for a suspected genetic disease at RCIGM as positive controls, the BeginNGS assay, which shares many overlapping gene targets with the diagnostic test, was able to achieve 99.1 percent recall in these samples.
The study also adopted a computational method called prequalification to help minimize false positives for the BeginNGS test. The method leverages a so-called purifying hyperselection phenomenon from evolutionary biology, which acts to decrease the frequency of causal diplotypes associated with severe childhood genetic disorders in elderly persons.
“If you have a severe childhood genetic disorder variant, that variant is unlikely to be present in healthy adults,” Wright explained. “We use that genetics framework to say that this variant is too common, it should be excluded from our analysis.”
By studying the genomes of middle-aged and elderly subjects, including 469,902 UK Biobank participants and 141,046 Mexico City Prospective Study participants, the RCIGM research subjects were able to identity and filter out variants from the BeginNGS assay, leading to a 97 percent reduction in false positive results.
The second paper described the results of a pilot clinical trial, for which the RCIGM researchers enrolled 120 infant patients in the NICU who were not under consideration for rapid diagnostic genome sequencing. In addition to the BeginNGS test, each infant received two index tests: California state newborn screening and rapid diagnostic genome sequencing.
Overall, the study demonstrated the safety of the BeginNGS test, which did not show any false positive or false negative results compared with the two index tests. “That was a great finding that encouraged us that the BeginNGS test was performing at an acceptable or optimized level,” Wright said.
Also, to the researchers' surprise, the results revealed that roughly 30 percent of the newborns sequenced and analyzed in the study had reportable genetic findings, even though their clinician did not anticipate that the infant would be a candidate for whole-genome sequencing, according to Wright. “This highlights that the NICU population is really undertested,” she noted.
Currently, the BeginNGS test screens for 53,575 variants among 342 genes that relate to 412 severe childhood genetic diseases with 1,603 efficacious therapies. As evidence emerges that early treatment improves or does not improve outcomes for certain conditions, phase three of BeginNGS, which is an adaptive trial, will add or remove these genetic disorders from the test, Wright said.
Carried out using the Illumina NovaSeq, the BeginNGS test targets a sequencingcoverage of about 35X, with a turnaround time of 14 days, she said.
Despite the potential promises of WGS for newborn screening, the economics remain to be determined. So far, funding for the project comes from BeginNGS consortium members and RCIGM's institutional support, according to Wright. RCIGM declined to disclose the per-sample cost of the BeginNGS test.
BeginNGS is not the only project hoping to foster the adoption of WGS-based newborn screening. In the US and across the world, a slew of pilot newborn genome sequencing projects have been ongoing to evaluate the feasibility and utility of genome sequencing for newborn screening.
Still, Wright thinks there is a place for traditional biochemistry-based newborn screenings carried out by public health labs. BeginNGS was “never meant to replace state newborn screening but rather be a supplement” to the existing newborn screen tests, she said.
“We view ourselves as catalysts,” Wright said. “The idea of having a newborn screening [test] that's widely available to any family is the goal.”