Large-scale Studies Needed to Guide Newborn Screening for Rare Diseases

Despite the known potential benefits of newborn screening, the exact long-term clinical benefits and cost-effectiveness in large cohorts remain uncertain due to a lack of large-scale longitudinal research.

Although newborn screening (NBS) for diagnostic biomarkers can provide a significant advantage to providers and patients by identifying treatable rare diseases before clinical manifestation, large-scale studies of its utility and cost-effectiveness are still lacking.

To optimize NBS programs and overcome their limitations, a review published in Journal of Inherited Metabolic Disease suggests performing longitudinal research and forming a collaborative international framework to optimize NBS on a global scale.

NBS aims to allow for preemptive management of detectable diseases ahead of clinical symptom manifestation based on biomarkers. In existence for more than 50 years, as technical advances in diagnostics are made, NBS programs can continually expand.

“Especially NBS programs have the potential to identify individuals with rare treatable conditions at an early stage, to prevent a diagnostic odyssey, to shorten the time to introduction of disease-changing therapies, and to improve health, development, and life expectancy,” the review authors wrote. “Therefore, they are considered an important measure of secondary disease prevention and as one of the greatest advances of modern public health, with significant individual, socio-economic, and societal benefits.”

Although studies have highlighted NBS’ benefits, they have also noted limitations, such as that some diseases have poorly understood natural histories and heterogeneous phenotypes. Disease severity can also be difficult to prognosticate accurately based on biomarker identification ahead of clinical symptoms, and treatment decisions can be difficult in patients with ambiguous screening and confirmatory test results.

There is also a lack of international universally adopted standards for population screening, meaning NBS disease panels differ significantly among countries. The review authors suggest revising and extending screening protocol and creating transparent, objective tools to select the diseases included in screening panels. Considering the progress being made with large-scale sequencing technology, keeping panels up to date is of increasing importance.

The success of NBS depends on deep knowledge of the diseases included in a panel. This includes gene variations, phenotypic diversity, and differences among individual cases. While the accuracy of NBS testing has improved and diagnostic uncertainty reduced, knowledge gaps remain. Currently, most existing data include shorter follow-up periods and small or medium regional cohorts.

Defining phenotypes and grading disease severity based on biomarkers can also pose a challenge, leading to uncertainty about if a patient should be treated based on NBS findings. Adverse effects of unnecessary treatment or missed opportunities for treatment that could positively alter a disease’s course are both possibilities, especially in rare diseases that may only have data available from very few randomized controlled trials.

“Longitudinal follow-up of NBS cohorts with careful evaluation of prescribed treatments can fill this important gap, preferentially if combined with systematic evaluation of literature and guideline development,” the authors wrote.

Timely NBS is also becoming more important as the number of known inherited metabolic diseases (IMDs) expands. In one study, 14.7% of screened individuals experienced a neonatal metabolic decompensation before NBS results were available, at a median age of 4 days. Experiencing a metabolic decompensation was not necessarily indicative of poor long-term outcomes, but the authors note that none of the events occurred after positive NBS results were known. Improving the NBS diagnosis process and initiating sampling earlier, which many countries have already done, can help to address this issue.

Individuals who are screened, found to have IMDs, and treated can have better outcomes, but the authors note there are disease-specific variations and limitations to NBS. For example, some diseases do not have treatments that prevent progression, some can be missed by NBS, and some are only treatable through highly invasive procedures. Without comparison of pre-NBS cohorts and NBS cohorts, the health benefits of NBS can also be overestimated.

Considering the entire scope of NBS effects is also key. Although outcomes may be favorable for patients with IMDs screened via NBS compared with those who are not, the process and its outcomes may put stress on patients and their families. This can come in the form of intensive therapy regimens, a lifelong fear of decompensations, and even false-positive results. On a larger scale, NBS must be feasible to implement for the entire population and health care system in any given location. Optimizing NBS to make it manageable on all levels is crucial going forward.

Overall, the review highlights a need for further studies to fine-tune NBS to maximize its positive effects and minimize the potential negative effects. For NBS to continue improving and knowledge to continue expanding, long-term observation of large real-world NBS cohorts and evaluations of its benefits and limitations are warranted, the authors wrote.

“Despite their extreme high cost, long-term observational studies using patient registries are multipurpose tools for rare disease research and guiding screening strategy,” the authors wrote. “Since long-term data for a rare disease might not be assessable or very limited prior to the planned extension of NBS programs, premature decisions on the implementation of new NBS diseases potentially cause a treatment dilemma for individuals identified by NBS.”

The study authors propose an additional principle to influence all NBS programs: Follow cohorts of individuals screened by NBS systematically to better understand the natural history and phenotypic diversity of rare diseases and clarify questions regarding case definition, treatment guidelines, and the societal and economic benefits of NBS. Developing a federated network of existing registry infrastructures, including regional and national NBS cohort studies, could help overcome the current limits of NBS research.


Mütze U, Mengler K, Boy N, et al. How longitudinal observational studies can guide screening strategy for rare diseases. J Inherit Metab Dis. Published online April 29, 2022. doi:10.1002/jimd.12508