Natural History of Disorders Screenable in the Newborn Period (R01 Clinical Trial Optional) | PAR 25 227

Frequently Asked Questions (FAQs)

1) What is this NIH funding opportunity trying to accomplish?

This opportunity (PAR-25-227) supports research to strengthen what is known about the natural history of disorders that are already included in statewide newborn screening programs, as well as conditions that could reasonably be added in the future. The intent is to help families and clinicians have clearer, evidence-based expectations after an infant is identified through newborn screening, including when symptoms tend to begin, how they change over time, and how variable outcomes can be across patients.

2) What does "natural history" mean in the context of this grant?

In this context, "natural history" refers to describing and documenting how a condition develops and progresses over time, especially starting from very early identification through newborn screening. The focus is on the sequence and timing of symptom development, how clinical signs emerge, how quickly (or slowly) progression occurs, and which early findings predict later outcomes.

3) Why is newborn screening an important starting point for these studies?

Newborn screening can identify infants very early, often before obvious symptoms appear. That early identification creates an opportunity to track what happens next in a structured way and to reduce uncertainty about expected clinical course, monitoring needs, and care planning.

4) Which conditions are in scope for this opportunity?

The scope includes (a) disorders already included in statewide newborn screening programs and (b) conditions that could reasonably be added to newborn screening programs in the future.

5) What types of research questions does NIH want applicants to address?

Based on the description provided, NIH is looking for projects that address questions such as:

• When do specific clinical signs and symptoms typically begin after newborn screening identification?
• How do symptoms change over time (progression patterns, timing, and sequence)?
• How variable is the condition across patients (heterogeneity in presentation and outcomes)?
• Which early clinical or biological findings predict later outcomes?
• How do genetic, epigenetic, or environmental factors contribute to differences in outcomes?

6) Are clinical trials required under this announcement?

No. Clinical trials are described as optional. Applicants may propose purely observational natural history studies, studies that build the foundation for future trials, or projects that incorporate interventional components when appropriate.

7) What is the "major focus" called out in the opportunity description?

A major focus is careful characterization of the sequence and timing of symptom development. This includes mapping when clinical signs emerge and how they change over time to support better decisions about monitoring schedules, referral timing, and when to initiate interventions.

8) How can natural history data improve clinical care after a positive newborn screen?

The intent is for natural history evidence to translate screening results into timely, appropriate care rather than uncertainty. By clarifying typical symptom onset and progression and identifying early predictors of outcomes, clinicians can make more informed decisions about follow-up, referrals, and potential interventions, and families can receive more useful supportive and predictive information.

9) What is meant by genotype-phenotype correlation, and why is it emphasized?

Genotype-phenotype correlation refers to linking genetic variation (genotype) to how a disorder presents clinically (phenotype). The opportunity highlights this because the same screened disorder can look mild in one child and severe in another. Strong genotype-phenotype correlations can improve the ability to predict likely clinical course after a positive newborn screen.

10) Does the opportunity encourage studying factors beyond the primary disease gene?

Yes. The description explicitly encourages identifying genetic modifiers, epigenetic influences, and environmental contributors. These factors may help explain why outcomes differ across individuals, clarify underlying biological mechanisms, and potentially point toward new therapeutic targets or supportive strategies.

11) What kind of data outputs does NIH appear to want from funded projects?

The opportunity emphasizes producing comprehensive, longitudinal data that the field can use. It also describes strengthening or developing data systems such as longitudinal registries that track child and family outcomes after newborn screening.

12) What are the stated outcomes this work should enable?

The description lists several outcomes the supported knowledge should enable, including:

1. Clearer insight into underlying biological mechanisms
2. Better understanding of genetic and clinical heterogeneity and how phenotypes are expressed
3. Improved diagnostic accuracy
4. Stronger support for clinical trials through high-quality natural history benchmarks
5. Better prevention, management, and treatment of symptoms and complications
6. More useful predictive and supportive information for physicians and families
7. Development or strengthening of data systems such as longitudinal registries tracking child and family outcomes after newborn screening

13) How does this funding opportunity relate to future clinical trials and treatments?

Even when a project is not a clinical trial, natural history studies can create a baseline for evaluating new treatments and management strategies. With a well-described expected course of disease, researchers can compare outcomes against that benchmark rather than relying on fragmented case reports or short-term observations.

14) What grant mechanism is being used?

This is an NIH R01 funding opportunity.

15) Is this a discretionary grant opportunity?

Yes. The listing describes it as a discretionary grant opportunity using the NIH R01 mechanism.

16) What CFDA (Assistance Listing) number is associated with this opportunity?

The listing categorizes it under CFDA 93.865.

17) What topical category is this opportunity listed under?

The listing categorizes it under Health, Income Security and Social Services.

18) Who is eligible to apply?

Eligibility is broad. Eligible applicants listed include:

• State, county, and local governments
• Special districts
• Independent school districts
• Public and private institutions of higher education
• Federally recognized Native American tribal governments
• Tribal organizations
• Public housing authorities
• Nonprofits with or without 501(c)(3) status
• For-profit organizations (other than small businesses)
• Small businesses
• Other entities

19) Are specific institution types and community-based organizations explicitly included?

Yes. The listing explicitly calls out additional eligible applicant categories such as Alaska Native and Native Hawaiian Serving Institutions, Asian American Native American Pacific Islander Serving Institutions (AANAPISIs), Hispanic-serving Institutions, Historically Black Colleges and Universities (HBCUs), Tribally Controlled Colleges and Universities (TCCUs), faith-based and community-based organizations, regional organizations, and U.S. territories or possessions.

20) Can federal agencies apply?

Yes. The listing includes eligible federal agencies among the eligible applicant categories.

21) Can tribal governments that are not federally recognized apply?

Yes. The listing explicitly includes tribal governments that are not federally recognized as eligible applicants.

22) Are foreign (non-U.S.) organizations eligible?

Yes. The listing states that foreign (non-U.S.) organizations are eligible.

23) What is the original closing date shown in the listing?

The posted original closing date is 2028-01-07.

24) When was the opportunity created (as shown in the listing)?

The listing states the opportunity was created on 2024-11-06.

25) Is there an award ceiling listed?

No. The award ceiling is not specified in the provided listing.

26) Is the expected number of awards listed?

No. The expected number of awards is not specified in the provided listing.

27) If the award ceiling and number of awards are not listed, how should applicants interpret that?

The provided information indicates that applicants should rely on the full NOFO and NIH institute guidance for budget expectations and funding outlook, since the listing does not specify an award ceiling or expected number of awards.

28) What is the practical emphasis of the opportunity beyond publishing descriptions?

The intent is to produce organized evidence that directly improves care pathways and research readiness. This includes comprehensive longitudinal data, improved prediction and diagnostic accuracy, stronger natural history benchmarks for evaluating interventions, and development or strengthening of longitudinal registries and related data systems.