Estimates from the early part of this millennium reveal that U.S. adults receive approximately half of the health care services recommended by committees such as the U.S. Preventive Services Task Force, the Community Preventive Services Task Force, and the Advisory Committee on Immunization Practices. The Affordable Care Act was enacted to help close the gap between the number of health care services recommended and the number of screening and other preventive services received routinely in the population. More specifically, Title IV of this law is focused on Prevention of Chronic Diseases and Improving Public Health by providing improved access to clinical preventive services. In December 2017, the U.S. Preventive Services Task Force published a report on clinical preventive services that highlights key evidence gaps for evidence-based screening modalities and for specific populations undergoing screening. Based on an evaluation of current gaps from research and reports, the National Institutes of Health (NIH) have identified research focused on increasing the uptake of evidence-based screenings for diverse adult populations as the primary focus of this funding opportunity.

Background
Although the focus of this funding opportunity is on increasing uptake of evidence-based screening for diverse populations, it is important to understand the past decade’s trajectory of use of clinical preventive services, of which, screening services are a major component. Almost a decade after the enactment of policy designed to improve preventive care, several hurdles remain. While some improvements in utilization of screening and preventive services have been observed, those improvements are generally seen among insured compared to uninsured populations. Utilization also varies by age. Fewer evidence-based screening services are recommended for young adults (ages 18-26) than for younger and older populations. This group has been relatively overlooked in relation to guidelines for preventive services, and they are the adult age group most likely to be uninsured. Issues unique to young adults have not been addressed explicitly within most guidelines because guidelines that include adolescents and adults seldom provide specific suggestions for young adults. State level evidence suggests that young adults have low rates of preventive services generally (16.7%-50.6%).

A national study that examined differences in Medicaid expansion vs. non-expansion states provides insights into factors influencing those disparities. The study found that, among adults up to age 64, those living below the poverty level (household income < 100% of FPL) and living in a Medicaid expansion state were more likely to have health insurance coverage, a usual source of care, routine check-ups, higher levels of breast, cervical, and influenza screenings and less likely to experience unmet health care needs because of cost. Similar results were observed for persons living above the federal poverty level in Medicaid expansion states versus non-expansion states. As a result, there appears to be a prevention services gap for adults living in non-expansion states. This evidence suggests that context serves as an important determinant of service utilization.

Among older adults (age 65 and older), the Medicare annual wellness visit was designed and implemented to promote evidence-based preventive care and address health risks in aging patients. These wellness visits incorporate screening for depression and fall risk that may exceed the scope of other preventive visits. Despite Medicare coverage for preventive services, increased use of preventive screening services has been modest to none within the past decade.

In addition, service delivery settings and allied health or non-traditional healthcare providers may be important determinants of uptake of recommended adult preventive screening services. In recent years, investigators have begun to explore the effects of providing preventive screenings outside of the usual clinical setting and by diverse allied health or non-traditional health care providers as one approach to increasing uptake. These settings include: pharmacies, colleges/universities, churches, beauty shops, barber shops, and other community settings. Furthermore, persistent gaps in rates of screening in rural compared to urban populations reflect the well documented challenges of providing clinical services, including screening, in rural settings. Studies have explored the use of a wide range of allied health and other providers in those settings including: lay health advisors/promotoras, traditional Native American healers, nurses, social workers, and pharmacists. Research has highlighted the need to consider the broader community context, both in terms of diverse settings and alternative providers, to ensure broader reach for evidence-based services (including screening) across the care continuum. The complex and multi-level environment in which patients receive care contributes to the likelihood that patients may get lost in the transitions of care and not complete the full process of screening.

U.S. populations are experiencing sex, racial and ethnic disparities in preventive screening across the adult lifespan. There is evidence that black and Hispanic young adults, as well as adults in other age categories fare better than whites in the receipt of a number of recommended preventive services. However, there are still high priority evidence gaps related to screening for chronic diseases among diverse populations such as African Americans (e.g., breast and prostate cancer screening). There are sex differences in preventive screening service utilization among young adults such that males are less likely than females to receive services. While existing research has documented a range of factors influencing disparities in receipt of screening across the continuum of the adult lifespan, recent research gaps have identified the need for studies designed to better understand mechanisms of disparities (e.g., demographic, social, cultural, place-based, or economic) in screening services across diverse populations and barriers to refine interventions designed to reduce disparities.

Scope of Research
Institutes within the NIH have separately advanced FOAs related to either the increased use of recommended preventive screenings or overuse of specific screenings in target adult populations. These initiatives are very specific to each Institute and Center (IC) mission area. However, as common risk factors are being identified for many common diseases and as more evidence-based screening interventions are identified, trans-NIH efforts to advance this research may advance more rapid exchange of insights on effective approaches across different disease areas. Therefore, the topics being addressed under this FOA are most appropriate for a trans-NIH FOA effort that addresses the interests of multiple NIH ICs. In addition, because these topics are relevant to prevention across NIH, the development of this FOA is being coordinated by the NIH Office of Disease Prevention.

Priority Areas

National Cancer Institute (NCI)
NCI addresses uptake of cancer screening among all populations and encourages research in screening that fills gaps in the science base regarding disparities among diverse populations. Studies are needed that understand screening as a process, rather than a single encounter. As a process, screening focuses on linking different healthcare entities that emphasize monitoring the context of care delivery for patients, from screening through treatment. Research is needed that focuses on multiple levels of the healthcare system that includes two or more levels of patients, providers, teams, clinic facilities, healthcare organizations. Areas of interest include, but are not limited to:

• Develop and/or test multilevel interventions to promote evidence-based screening identifying characteristics of the healthcare delivery context (e.g., at the patient, provider, teams, clinic facility or healthcare organization level) that might enhance or inhibit improvements to care by studying: a) promotion of HPV screening, teamwork processes, shared decision making, situational awareness, follow-up to abnormal cancer screening tests, and partnership with patients; and b) mechanisms by which multilevel characteristics operate to enhance or inhibit provision of evidence-based screening.
• Develop and/or test healthcare delivery intervention approaches to modify social determinants of health to improve delivery of evidence-based cancer screening.
• Develop and/or test implementation strategies to increase uptake of evidence-based cancer screening and follow-up practices, targeting at least two levels: patient, provider, teams, clinic facility and/or healthcare organization-level.
• Develop and/or test multilevel strategies to implement evidence-based screening practices in low-resource or underserved areas, with an emphasis on follow-up and treatment.
• Develop and/or test multilevel strategies to adapt, implement, and/or sustain evidence-based screening and follow-up practices in clinical settings.

National Institute on Aging (NIA)
The National Institute on Aging encourages experimental, observational, or interventional studies focused on adults in midlife and at older ages. Where this FOA addresses screening, other FOAs may be used to address over-screening (for example PA-18-005).

Areas of interest include, but are not limited to:

• Evaluate the impact of a personalized preventive care program on screening, health care utilization and expenditure trends
• Evaluate the impact of programs to encourage the use of annual wellness visits, overall and through mechanisms adapted to underserved populations and the practices that serve them
• Evaluate low-cost interventions designed to improve physician adherence to recommended screening guidelines to increase use of preventive services and improve health outcomes
• Evaluate approaches that would enable screening interventions to be focused on those at particular life stages or on the entire life course
• Determine how linkages and more coordinated screening activities across various healthcare and community settings could result in more efficiencies and improved health outcomes

New data collection, novel interventions, or secondary analysis of existing datasets, such as the Health and Retirement Study or the Midlife in the U.S. (MIDUS) Study, that contain rich data on adults targeted by this FOA are encouraged. For a list of datasets sponsored by the NIA, see: http://www.nia.nih.gov/research/dbsr/publicly-available-databases-aging-related-secondary-analyses-behavioral-and-social.

National Institute on Alcohol Abuse and Alcoholism (NIAAA)
The United States Preventive Services Task Force (USPSTF) recommends that primary care providers screen all adults and conduct brief counseling for those who misuse alcohol, as it found evidence in support of screening and brief intervention (SBI) delivered in primary care to adults. However, disparities in such screening have been found to exist, as Black non-Hispanics report significantly lower prevalence of screening than do white non-Hispanics and college graduates report significantly higher prevalence of screening than do those with a high school degree or less. Moreover, while many validated instruments already exist for alcohol screening, research indicates that many providers who do report screening for alcohol misuse do not use screening tools that are capable of detecting the full spectrum of alcohol misuse i.e., they may be asking about drinking but are not screening or they do not engage in follow-up questions, or they are unfamiliar with typical standard drink equivalents in discussing drinking with patients. Furthermore, screening for alcohol use is performed inconsistently by emergency department (ED) physicians. Other populations that likely would benefit from enhanced screening strategies are pregnant women and those in elderly care. Beyond the screening process itself, provision of brief advice about drinking and subsequent referral to specialty treatment have been found to be inconsistently provided by primary care and ED providers.

Areas of interest include, but are not limited to:

• Establish the feasibility and efficacy of providing alcohol misuse screening opportunities among: nonwhite populations, those with lower educational levels, and pregnant women
• Establish the feasibility and efficacy of providing alcohol misuse screening opportunities to those in: elderly care settings, primary care settings, emergency departments, and community settings.
• Increase the consistent use by primary care practitioners, ED physicians, and others of appropriate screening tools with established capability of detecting the full spectrum of alcohol misuse.
• Increase primary care and ED and community-based providers consistent provision of brief advice about drinking and referral to specialty treatment for those patients screening positive for alcohol misuse.

National Institute of Dental and Craniofacial Research (NIDCR)
The dental office is a primary care setting that provides an opportunity for oral health practitioners to conduct preventive general health services, such as evidence-based screenings. Many adults in the U.S. may have a dental visit in a given year, but not a routine medical visit. Therefore, evidence-based health screenings in dental offices provide opportunities to identify individuals with undiagnosed or progressing chronic conditions, beyond those conditions specific to the head and neck region. Several studies have demonstrated the feasibility of conducting evidence-based screenings in the dental setting for chronic conditions, such as diabetes. Additionally, previous research indicates acceptability of screening for chronic conditions in a dental setting to both dental professionals and patients. NIDCR encourages observational studies focused on implementing screening and referral for diabetes, hypertension, and/or Human Immunodeficiency Virus (HIV) infection (screenings that have received an evidence-based grade by the U.S. Preventive Services Task Force) by oral health professionals in a dental setting. These studies could examine aspects of screening across the care continuum from: risk assessment, to detection, through initial referral, and seeking care with medical providers. Research that explores improving uptake of screening, referral, and follow-up with medical providers would be encouraged.

Areas of interest include, but are not limited to:

• Improve the provision and uptake of screening in diverse dental settings, including those settings that target underserved populations,
• Explore the willingness/acceptability of screening for medical conditions by dental professionals,
• Improve rates of referral following screening,
• Determine the degree to which patients follow-up with and visit a physician/medical provider after being screened and referred, and
• Enhance screening and referral using technology (such as, integrated Electronic Health Records and clinical decision support systems).

National Institute on Drug Abuse (NIDA)
The United States Preventive Services Task Force (USPSTF) has concluded that the current evidence for screening adults for illicit drug use is insufficient, and does not recommend screening in primary care for adults (including pregnant women). There is a need for research to contribute to the evidence base on screening for illicit drug use and substance use disorder, prescription drug and opioid misuse, and opioid use disorder in adults, including pregnant women in primary and other healthcare settings. In addition, there is a need for research on screening in adults in settings beyond primary care, in settings where young adults work, access community services, engage in social and recreational activities, and particularly in settings that are utilized by vulnerable and at-risk populations. Of particular interest is research that focuses on screening for opioid misuse and opioid use disorder and linkage to prevention and treatment services.

Areas of interest include, but are not limited to:

• Test models for healthcare and other settings for screening and brief prevention and treatment interventions for illicit drug use and substance use disorder, prescription drug and opioid misuse, and opioid use disorder as well as linkage to prevention and treatment services.
• Test models or strategies for screening and linkage to prevention and treatment services for diverse and vulnerable populations in healthcare settings and systems (primary care, emergency departments, urgent care, school and college health centers) and other systems (workplace, community, recreational, social services, criminal justice).
• Test models and strategies for integrating screening and referral or linkage to prevention and treatment services into healthcare systems/practices (e.g., including algorithms, decision tools, reminders), and also test strategies for sustainability.
• Validate existing or new instruments for screening for illicit drug use and substance use disorder, prescription drug and opioid misuse, and opioid use disorder in healthcare and non-healthcare settings.
• Test innovative and new technologies to enhance screening and linkage to prevention and treatment services in healthcare and other settings.

National Institute on Mental Health (NIMH)
NIMH is interested in studies of the effectiveness and implementation of mental health screening delivered in approaches that include detection of symptoms, referral for diagnosis and follow-up for subsequent engagement in treatment when indicated. Populations of interest include but are not limited to those experiencing inadequate detection of symptoms, limited access to or engagement in mental health treatment. These populations may also include but are not limited to people from underserved racial, ethnic, and language-minority groups; those living in rural areas or impoverished communities; refugees and immigrants; individuals from sexual/gender minority groups; or other underserved groups. Relevant screening sites may include non-specialty and community-based settings, or novel settings or providers when justified. New uses of technology and sustainable approaches designed for integration into existing organizational practices or systems are encouraged. Investigators must first demonstrate existing evidence-based approaches to screening, referral, and follow-up are ineffective, not available, and/or not delivered in the target population or that there are clear differences in outcomes (in the wrong direction) associated with implementing existing evidence-based approaches in the target population.

Applications that test or compare provider- or system-level interventions designed to promote uptake of screening or interventions to promote engagement/continuity of service use should detail plans to explicitly address whether the intervention engages the target(s)/mechanism(s) presumed to underlie the intervention effects (the mechanism(s) that account for changes provider- or patient- behavior), consistent with the NIMH experimental therapeutics approach (http://www.nimh.nih.gov/about/director/2012/experimental-medicine.shtml). Applications should address: (1) the empirical basis for the intervention target(s)/mechanism(s), i.e., the empirical evidence linking the target(s)/mechanism(s) to the patient-, provider- or system-level behaviors/processes that the intervention seeks to ultimately improve; (2) plans for assessing engagement of the target(s)/mechanism(s); and (3) analyses that will be used to examine whether the intervention engages the target(s)/mechanism(s) and whether intervention-induced changes in the target(s)/mechanism(s) are associated with clinical benefit.

Effective services that support prevention and treatment of mental illness have the potential to reduce morbidity and mortality associated with intentional injury (i.e., suicide attempts and deaths, see: www.suicide-research-agenda.org). Lack of attention to the assessment of these outcomes has limited our understanding regarding the degree to which effective mental health interventions might offer prophylaxis. Accordingly, where feasible and appropriate, NIMH encourages effectiveness research that, includes assessment of suicidal behavior in order to advance understanding of how effective prevention and treatment of mental disorders might impact suicide relevant outcomes.

National Institute on Minority Health and Health Disparities (NIMHD)
NIMHD is interested in projects that address screening for conditions that are more prevalent in health disparity populations and/or for which health disparity populations have disproportionately low rates of screening. Health disparity populations include African Americans/Blacks, Hispanics/Latinos, American Indians/Alaska Natives, Asians, Native Hawaiians and Other Pacific Islanders, socioeconomically disadvantaged populations, underserved rural populations, and sexual and gender minorities. Projects are encouraged that encompass multiple domains (e.g., biological, behavioral, socio-cultural, environmental, physical environment, healthcare system) and multiple levels (e.g., individual, interpersonal, community, societal) to understand screening behavior and effectiveness (see the NIMHD Research Framework, https://www.nimhd.nih.gov/about/overview/research-framework.html).

Examples of potential topic areas include but are not limited to:

• Multilevel intervention to increase screening rates among health disparity populations
• Clinical and pragmatic trials of efficacy and effectiveness of existing screening methods, particularly those recommended by the US Preventive Services Task Force (USPSTF, https://www.uspreventiveservicestaskforce.org/), that have not been adequately tested or implemented in health disparity populations.
• Novel mechanisms or technology to address screening gaps in underserved health disparity populations.
• Development and testing of new screening methods or guidelines that better capture disease risk for health disparity populations.
• Comparative effectiveness of different interventions to increase screening rates among health disparity populations

Office of Disease Prevention (ODP)
The Office of Disease Prevention encourages applications that have promise for increasing uptake of adult screening interventions targeting diverse populations. These interventions should have strong implications for disease prevention and make use of innovative design, measurement, and analytic methods relevant to the overall objectives of this funding opportunity announcement. Applications must also be relevant to the objectives of at least one of the participating NIH Institutes and Centers (IC) listed above. ODP does not award grants. Please contact one of the IC program contacts listed for questions related to funding.

1. Eligible Applicants

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)

• Eligible Agencies of the Federal Government

• U.S. Territory or Possession

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

Applicant organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

2. Cost Sharing

3. Additional Information on Eligibility

Number of Applications

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101)

1. Requesting an Application Package

Buttons to access the online ASSIST system or to download application forms are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

All instructions in the SF424 (R&R) Application Guide must be followed.

The following modifications also apply:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

3. Unique Entity Identifier and System for Award Management (SAM)

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

4. Submission Dates and Times

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday , the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement .

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

7. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact a Scientific/ Research Contact at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF424 (R&R) Application Guide.

Important Update: See NOT-OD-18-228 for updated review language for due dates on or after January 25, 2019.

1. Criteria

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.

Significance

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as they key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

In addition, for applications involving clinical trials
Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

In addition, for applications involving clinical trials
With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

Innovation

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

In addition, for applications involving clinical trials
Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?