ROLE OF SLEEP AND SLEEP-DISORDERED BREATHING IN METABOLIC SYNDROME RELEASE DATE: October 16, 2002 RFA: RFA-HL-03-008 National Heart, Lung, and Blood Institute (NHLBI) (http://www.nhlbi.nih.gov/) National Institute on Aging (NIA) (http://www.nia.nih.gov/) Letter of Intent Receipt Date: January 13, 2003 Application Receipt Date: February 11, 2003 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism(s) of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements (if included) o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations: PURPOSE OF THIS RFA The goal of this Request for Applications (RFA) is to elucidate the relationship of sleep deprivation and sleep-disordered breathing (SDB) to characteristics of the metabolic syndrome including obesity, high blood pressure, dyslipidemia, insulin resistance, and vascular inflammation. Specific objectives include identifying the pathophysiological mechanisms and genetic risk factors linking sleep deprivation and SDB to these characteristics. RESEARCH OBJECTIVES Background The high prevalence of metabolic syndrome, SDB, and sleep deprivation has major public health implications. Recent estimates suggest that 20-25% of the U.S. population exhibit symptoms of the metabolic syndrome and are at increased risk of cardiovascular complications. SDB including loud snoring, increased upper airway resistance, and repetitive pauses or decrements in breathing during sleep, is estimated to affect 5-10% of middle-age adults and 20-30% of the elderly. Children with academic difficulty exhibit an unusually high prevalence of SDB symptoms. Sleep deprivation due to lifestyle and chronic illness is thought to be widespread in all age groups. Average sleep duration of the normal working population has decreased from about 9 hours per night in 1910 to about 7.5 hours currently, a trend that is inverse to that of obesity. Both SDB and sleep deprivation are associated with excessive daytime sleepiness, impaired cognitive performance, and an increased risk of accidents. Recent findings suggest that SDB and sleep deprivation are associated with specific molecular, anatomical, and pathophysiological abnormalities affecting brain, kidney, and vascular function. However, the relationship of SDB and sleep deprivation to other physiological systems contributing to normal health and development are not well understood. Recent findings suggest that the metabolic syndrome, SDB, and sleep deprivation may share similar pathophysiological, prothrombotic and proinflammatory states. SDB has been identified as a potentially important risk factor for cardiovascular abnormalities including overactivity of the sympathetic nervous system, decreased nocturnal dipping of blood pressure, blunted heart rate variability, and possibly arrhythmia. SDB produces repetitive episodes of blood oxygen desaturation (hypoxemia) and sleep disturbance (electroencephalographic arousal) that disturb restorative physiological patterns linked to cycles of sleep and wakefulness. Several lines of evidence indicate a relationship between sleep disturbance, abnormalities in the circadian secretion of neuroendocrine hormones, and a diminished ability to regulate blood glucose that characterizes pre-diabetic conditions. Improving sleep quality in patients with heart failure seems to reduce sympathetic outflow and preserve myocardial function. Fasting glucose and insulin levels are higher than normal in patients with SDB, and SDB severity correlates with indices of glucose metabolism. Proinflammatory cytokines associated with insulin resistance and vascular disease are also higher in patients with SDB. SDB patients with diabetes exhibit significantly less deep (REM) sleep; and there is a close association between the prevalence of diabetes and SDB severity. SDB treatment using nasal continuous positive airway pressure (CPAP) seems to improve insulin sensitivity in some obese diabetic patients but it is unclear whether SDB is independently associated with insulin resistance. Chronic sleep restriction may increase susceptibility to the metabolic syndrome independent of SDB or other sleep disorders. Sleep deprivation in normal healthy young adults results in marked alterations of glucose metabolism in the absence of breathing abnormalities. The state of "sleep debt" per se is associated with increased sympathetic nervous activity and abnormalities in endocrine function. Chronic partial sleep deprivation decreases the normal nocturnal rise in thyrotropin, increases cortisol secretion, and decreases nocturnal growth hormone secretion, similar to patterns seen in older adults. Alterations in the pattern of growth hormone and cortisol exposure may play a role in weight gain and the development of insulin resistance. Obesity is associated with depressed respiratory control. SDB patients have greater amounts of visceral fat compared to obese non-SDB patients, and indices of SDB correlate with visceral fat. Women appear less susceptible to the development of SDB compared to men, and this may be related to a higher preponderance of subcutaneous versus visceral fat for a given level of obesity. Emerging evidence suggests that circulating factors secreted primarily from visceral fat link SDB and cardiovascular disease. Leptin, a fat cell-secreted hormone, influences food intake by signaling energy balance, and may have opposing effects on vascular tone by stimulating both central sympathetic tone to vascular beds leading to vasoconstriction and peripheral vascular nitric oxide production leading to vasodilatation. SDB patients exhibit higher leptin levels than expected based on the severity of obesity, and treatment of SDB with CPAP appears to normalize leptin levels independent of weight changes. A relative deficiency in leptin, or leptin resistance, may play a role in the pathophysiology of SDB and cardiovascular disease. Other circulating fat-secreted factors, such as TNF-alpha and interleukin-6, promote sleep, and seem to exacerbate symptoms of poor sleep when elevated in association with SDB. Elevated levels of TNF-alpha can also stimulate leptin secretion and contribute to dyslipidemia. Apolipoprotein E epsilon4 (APOE e4), a polymorphism of a key protein in lipid metabolism, and linked to cardiovascular disease, diabetes, and Alzheimer=s disease, appears to be associated with increased severity of SDB symptoms in some populations, suggesting a possible common pathophysiological pathway involving lipid metabolism. Abnormalities in endothelial function are associated with SDB. Frequent intermittent episodes of hypoxia and reoxygenation associated with SDB are a potent stimulus for oxidative stress. The production of reactive oxygen species (ROS) has been implicated in vascular complications such as retinopathy, nephropathy, cardiovascular disease, and pathologies associated with aging. ROS levels are elevated in SDB and lowered by CPAP treatment. Whether SDB can account for the elevated levels of ROS associated with obesity is unclear. Nitric oxide signaling is a potent regulator of vascular tone altered by intermittent hypoxia. SDB is associated with a decreased level of circulating nitric oxide and blunted endothelium-dependent vasodilator responsiveness to acetylcholine and bradykinin. This endothelial dysfunction appears to be reversed by CPAP therapy. Abnormalities in vascular reactivity associated with SDB may predict atherosclerosis and its complications. Alterations in circulating levels of ROS and nitric oxide can also affect chemosensitivity to hypoxia and hypercapnia, respiratory control, and sleep. Concomitant with diminished vasodilator responsiveness, SDB patients exhibit increased levels of the vasoconstrictor, endothelin-1, and vascular endothelial growth factor (VEGF), an angiogenic cytokine implicated in diabetic vascular complications, with reductions in both after CPAP therapy. The VEGF gene is mainly stimulated by hypoxia through the mediation of hypoxia-inducible factor (HIF). HIF may be responsible for inducing an array of hypoxia-sensitive genes as a result of SDB and intermittent hypoxia including those encoding erythropoietin and glycolytic enzymes. Thrombotic events believed to a major cause of heart attack are more likely to occur during sleep. SDB-induced hypoxic stress and metabolic abnormalities stemming from sleep deprivation may modulate circulating inflammatory mediators causing accelerated atherogenesis. SDB is associated with increased expression of pro-inflammatory mediators, adhesion molecules, and increased ROS production in some monocyte and granulocyte subpopulations. CPAP appears to decrease platelet activation and aggregation suggesting that SDB contributes to a prothrombotic environment. Research Scope This RFA seeks to develop a better understanding of relationships between sleep deprivation, SDB, and the metabolic syndrome with the goal of reducing the risk of cardiovascular complications and age-associated pathologies. Listed below are examples of studies that would be responsive to this program. These are only illustrative examples and applicants are encouraged to consider other topics consistent with the goals of this program. Not all areas need to be addressed in a single application. o Elucidate the effects of partial sleep deprivation or SDB on pathophysiological mechanisms of lipid and glucose metabolism that influence the risk of obesity, diabetes, or neurodegenerative disorders in human subjects or in well-characterized animal models. o Determine whether SDB plays a role in the pathophysiological mechanism by which insulin resistance increases endothelial dysfunction, which leads to hypertension, all hallmarks of the metabolic syndrome. o Characterize the effect of sleep deprivation or SDB on cardiovascular disease or neurocognitive outcomes using existing epidemiological cohorts (nested case-control study) in which risk factors for the metabolic syndrome were determined as a major focus of the parent investigation. o Elucidate the relative role of SDB-related intermittent hypoxia and sleep disturbance in producing abnormalities in atherogenesis, prothrombotic or proinflammatory mediators, sympathetic neural activity, or causing cardiovascular disorders, such as hypertension, that contribute to the metabolic syndrome. o Identify genetic, racial, ethnic, gender, or age-dependent factors influencing the pathophysiological effects of partial sleep deprivation or SDB on potential risk for the metabolic syndrome. o Elucidate the mechanisms through which sleep deprivation or SDB affect fat- secreted factors contributing to the risk of the metabolic syndrome. o Elucidate effects of sleep deprivation or SDB occurring during critical phases of early development and leading to increased risk for the metabolic syndrome in older children or older adults. o Elucidate potential links between abnormalities in chemosensitivity or the regulation of breathing and disorders characteristic of the metabolic syndrome. o Elucidate functions of the biological clock or other neural mechanisms regulating sleep that influence the relationship between individual or age- dependent susceptibility to sleep deprivation and risk factors for the metabolic syndrome. MECHANISM OF SUPPORT This RFA will use the NIH research project (R01) award mechanism. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Future unsolicited, competing-continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is September 30, 2003. This RFA uses just-in-time concepts. It also uses the modular budgeting format. (see http://grants.nih.gov/grants/funding/modular/modular.htm). All applications must be in the modular format. FUNDS AVAILABLE The NHLBI intends to commit approximately $3 million, and the NIA intends to commit approximately $375,000 in FY2003 to fund six to eight new grants in response to this RFA. An applicant may request a project period of up to four years and a budget for direct costs of up to $250,000 per year. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the NHLBI and NIA provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. Since the total costs for a subcontract or consortium are included in the direct cost request, one or more additional modules of $25,000 above the cap may be requested for the facilities and administrative costs associated with third party agreements. Modules requested for this purpose must be clearly identified in the budget justification section of the application, and will be restricted for this purpose only at the time of award. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from under-represented racial and ethnic groups as well as individuals with disabilities are encouraged to apply for NIH programs. SPECIAL REQUIREMENTS Restrictions and Exclusions To be responsive to this announcement, applications must propose hypothesis- driven studies that focus on elucidating the effects of sleep deprivation or SDB on characteristics of the metabolic syndrome and related cardiovascular or cerebrovascular outcomes. For the purpose of this RFA, the metabolic syndrome includes emerging risk factors such as lipoprotein, homocysteine, prothrombotic and proinflammatory factors, impaired glucose metabolism, and subclinical atherosclerotic disease. Sleep deprivation is defined as sleep restriction independent of other sleep disorders or sources of disturbed sleep. Studies focused on partial sleep deprivation and having the potential to facilitate epidemiological studies of life-habit risk factors are encouraged. Studies to identify genetic markers of this interrelationship will also be responsive. Studies proposing the use of nonmammalian species or in vitro preparations should clearly establish the relationship of these models to the goals set forth in this RFA. The elucidation of environmental and psychosocial factors that cause sleep deprivation such as life-style behaviors, shift work, rapid time zone changes, stress, cultural and socioeconomic factors will not be supported under this RFA. Studies of sleep deprivation secondary to chronic illness, alcohol abuse, pain syndromes, cancer, mental disorders, and the relationship of sleep to behavioral endpoints such as workplace performance would also be unresponsive to this RFA. Applications focused on the development of methodology, interventions, large clinical studies, or the establishment of large epidemiological cohorts that collect data for future studies are not within the scope of this program. Collaborations and consortia promoting interdisciplinary approaches between scientists studying cardiology, vascular biology, pulmonology, sleep medicine, hematology, neuroimmunobiology, infectious disease, endocrinology, genetics, and neurophysiology are strongly encouraged. In such cases, each participant's contribution should be identified and well-integrated into the overall experimental design. Investigator Coordination Meetings Upon initiation of the program, periodic meetings may be organized to encourage the exchange of information among investigators who participate in this program. Travel funds for the principal investigator to attend a two-day meeting each year, most likely to be held in Bethesda, Maryland, must be included in the module calculation. Applicants must include a statement indicating their willingness to participate in these meetings. Applicants are encouraged to contact the program officials listed under INQUIRIES for further information. General Clinical Research Centers Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC program director or principal investigator should be included with the application. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about scientific/research issues to: Michael Twery, Ph.D. Division of Lung Diseases National Heart, Lung, and Blood Institute National Institutes of Health 6701 Rockledge Drive, MSC 7952 Bethesda, Maryland 20892-7952 Telephone: (301) 435-0202 Fax: (301) 480-3557 Email: Twerym@nhlbi.nih.gov Winnie Barouch, Ph.D. Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 10193, MSC 7956 Bethesda, MD 20892-7956 Telephone: (301)435-0560 FAX: (301)480-2849 Email: BarouchW@nhlbi.nih.gov Paul Sorlie, Ph.D. Division of Epidemiology and Clinical Applications National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 8176, MSC 7934 Bethesda, MD 20892-7934 Phone: (301) 435-0707 Fax: (301) 480-1455 Email: ps46f@NIH.GOV Carl E. Hunt, M.D. National Center on Sleep Disorders Research National Heart, Lung, and Blood Institute Rockledge II, Suite 10138 6701 Rockledge Drive Bethesda, MD 20892 Phone: (301) 443-0199 Fax: (301) 480-3557 E-mail: HuntC@nhlbi.nih.gov Andrew A. Monjan, Ph.D., M.P.H. National Institute on Aging 7201 Wisconsin Avenue, Suite C3C07 Bethesda, MD 20892 Telephone: (301) 496-9350 FAX: (301) 496-1494 Email: am39m@nih.gov o Direct your questions about peer review issues to: Anne Clark, Ph.D. Chief, Review Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Dr., Room 7214 (MSC 7924) Bethesda, MD 20892-7924 (20817 for express/courier service) Telephone: (301) 435-0270 FAX: (301) 480-0730 Email: clarka@nhlbi.nih.gov o Direct your questions about financial or grants management matters to: Robert Pike Division of Extramural Affairs National Heart, Lung, and Blood Institute National Institutes of Health 6701 Rockledge Drive, MSC 7926 Bethesda, Maryland 20892-7926 Telephone: (301) 435-0171 Fax: (301) 480-3310 Email: rp182p@NIH.GOV Linda Whipp Grants and Contracts Management Officer National Institute on Aging Gateway Building, Suite 2N212 7201 Wisconsin Avenue, MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-1472 FAX: (301) 402-3672 Email: whippl@nia.nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to Dr. Anne Clark at the address listed under WHERE TO SEND INQUIRIES. SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: All applications submitted to this RFA must use the modular budget format. Facilities and administrative costs associated with subcontract or consortium third party agreements can be requested with additional modules, using the modular budget format. The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step guidance for preparing modular grants. Additional information on modular grants is available at http://grants.nih.gov/grants/funding/modular/modular.htm USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package to: Center For Scientific Review National Institutes Of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application and all five collated sets of Appendix material must be sent to Dr. Anne Clark at the address listed under WHERE TO SEND INQUIRIES. APPLICATION PROCESSING: Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an Introduction addressing the previous critique. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NHLBI. If an application is not responsive to the RFA, staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next appropriate NIH review cycle. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NHLBI in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o Receive a second level review by the NHLBI and/or NIA National Advisory Council REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your application's overall score, weighting them as appropriate for each application. Your application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, you may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) SIGNIFICANCE: Does your study address an important problem? If the aims of your application are achieved, how do they advance scientific knowledge? What will be the effect of these studies on the concepts or methods that drive this field? (2) APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: o PROTECTIONS: The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. o INCLUSION: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below) o DATA SHARING: The adequacy of the proposed plan to share data. o BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: January 13, 2003 Application Receipt Date: February 11, 2003 Peer Review Date: June/July, 2003 Council Review: September, 2003 Earliest Anticipated Start Date: September 30, 2003 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities. REQUIRED FEDERAL CITATIONS MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at http://grants.nih.gov/grants/funding/children/children.htm. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://grants.nih.gov/grants/stem_cells.htm and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide the official NIH identifier(s)for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93.837, 93.838, 93.839, 93.233, and 93.866 and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284)(or other authorizations) and administered under NIH grants policies described at http://grants.nih.gov/grants/policy/policy.htm (cite other relevant policies) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92 (cite other relevant regulations). The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.


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