Newborn screening (NBS) is an important tool to improve human health—particularly for children with rare diseases who might benefit from early intervention. Yet in many countries, it can take years to generate the data and build the infrastructure necessary to add new conditions to NBS panels.

In the United States, health policymakers face an additional challenge in managing NBS programmes: while the federal government publishes general guidelines on newborn screening, individual states are free to choose which tests to include on state-sponsored panels. Because of this patchwork system, families may fall through the cracks if the newborn screening process where they live is not robust.

To help address these challenges, a team of researchers in North Carolina developed Early Check, a research platform that aims to shorten the timeline for evaluating new assays for NBS and supporting research in rare diseases [1]. Operating in partnership with the state’s newborn screening program and local university partners, it is currently offered to families as an optional research supplement to the state’s standard NBS protocols.

Lab Insights recently spoke with two representatives of the Early Check programme, who highlighted several key considerations that are essential for any NBS effort.

Assessing the benefit of early detection

For any condition to be considered in the Early Check research study, one of the first considerations is whether there is a reliable assay available to test for the condition. In order to keep their implementation timelines as tight as possible, the programme focuses primarily on evaluating, validating and implementing existing assays, rather than assay development.

“We have to know the landscape of laboratory science and understand which assays might be ready for evaluation for newborn screening,” says Dr Katerina (Kate) Kucera, lab director for the Early Check program at RTI International. “Some conditions are currently not ideal candidates for NBS primarily because there is no assay available.”

Another consideration is whether children and families will ultimately benefit from early diagnosis. Even if a disease can be detected accurately and cost-effectively, early detection may offer limited benefit if no therapy or intervention is available to alter the trajectory of the disease.

Assuming treatments or interventions are available, resources must be in place to prepare for the event that a newborn tests positive during the screening process. In the Early Check research programme, a positive research result triggers several actions: initial notification to the family, follow-up from a genetic counsellor, confirmatory testing for the condition, and connections to the clinical or behavioural experts who can help the family for that specific condition.

At launch, the Early Check team selected Fragile X syndrome (FXS) and spinal muscular atrophy (SMA), two conditions that were not included in newborn screening at the time but for which early intervention makes a real difference in a child’s development. Their evaluations of SMA [2] and FXS [3] are now complete.

Now, the team is currently screening for Duchenne muscular dystrophy (DMD) and related conditions, and is planning to launch a new research programme focused on three chromosome 15 imprinting disorders—Angelman syndrome, Prader-Willi syndrome, and Dup15q. The team is also exploring the potential uses of genome sequencing in newborn screening.

“We need to get the diagnosis earlier to be able to have maximum benefit for patients with Angelman syndrome,” says Dr Anne Wheeler, a public health analyst at RTI International and member of the Early Check program who spent years treating Angelman patients as a psychologist. There are also therapeutics in development for chromosome 15 disorders that would make early diagnosis even more important.

What are the key logistical issues?

As conditions are selected and resources assembled to deal with positive cases, the rest of the Early Check research programme becomes a matter of logistics. For example, in evaluating an assay, the Early Check team has to consider not only clinical accuracy but also cost and ease of use—is it an assay that could be widely adopted by labs that perform routine newborn screening?

To address cost, they are keenly interested in multiplexed testing. They are also looking into genome sequencing, which could open the doors for testing many conditions for which there are no other assays available. Both approaches could allow them to generate more answers from the dried blood spot samples they use.

“The more tests for different conditions you have, the more real estate you need in terms of blood,” Dr Wheeler notes. Ensuring a rapid and reliable process for getting samples from the hospital to the screening lab is also essential.

Funding, of course, is important too. Any research study needs steady funding to support lab work, follow-up testing, education for families, and more. “There is a lot of enthusiasm about the importance of early identification, yet bringing all the stakeholders together and creating a common goal for a research study that can be funded is something that we see as a challenge all the time,” Dr Kucera says.

With exciting new therapies for many rare diseases on the horizon, state NBS programmes should continue to improve over time, not only in terms of their breadth but also their quality and cost. By generating high-quality evidence on the efficacy of new assays, the Early Check research programme is making important contributions to this progress.

References:

[1] Bailey, D., Gehtland, L., Lewis, M., Peay, H., Raspa, M., Shone, S., Taylor, J., Wheeler, A., Cotten, M., King, N., Powell, C., Biesecker, B., Bishop, C., Boyea, B., Duparc, M., Harper, B., Kemper, A., Lee, S., Moultrie, R., Okoniewski, K., Paquin, R., Pettit, D., Porter, K. and Zimmerman, S., 2019. Early Check: translational science at the intersection of public health and newborn screening. BMC Pediatrics, 19(1). Access at: <https://bmcpediatr.biomedcentral.com/articles/10.1186/s12887-019-1606-4>

[2] Kucera, K., Taylor, J., Robles, V., Clinard, K., Migliore, B., Boyea, B., Okoniewski, K., Duparc, M., Rehder, C., Shone, S., Fan, Z., Raspa, M., Peay, H., Wheeler, A., Powell, C., Bailey, D. and Gehtland, L., 2021. A Voluntary Statewide Newborn Screening Pilot for Spinal Muscular Atrophy: Results from Early Check. International Journal of Neonatal Screening, 7(1), p.20. Access at:<https://www.mdpi.com/2409-515X/7/1/20>

[3] Okoniewski, K., Wheeler, A., Lee, S., Boyea, B., Raspa, M., Taylor, J. and Bailey, D., 2019. Early Identification of Fragile X Syndrome through Expanded Newborn Screening. Brain Sciences, 9(1), p.4. Access at:<https://www.mdpi.com/2076-3425/9/1/4>