K23 Grant Templates

From Wikipedia

I] THE CANDIDATE :

A] THE CANDIDATE's BACKGROUND : This should include the candidate’s career with respect to his/her educational degree, college, university, interests in focus of this research.

To be specific this is divided into following points.

a) INTEREST IN TOPIC: This should explain the source from where the candidate developed interest in research and specifically the related topic. This should create an impact that the candidate has real vested interest in the research topic.

Example: During my two years of postgraduate education at the University of Michigan, I focused on clinical training and developing my laboratory skills. My interest in the immunocompromised host began in my second year during advanced training in infectious diseases. I became interested in patients who received chemotherapy and immunosuppressive therapies and the immunologic complications that ensued.

b) PERSONAL HISTORY AND RESEARCH: This gives the reader the complete idea of candidate’s journey through research field, which should include the beginning of career in research field and experiences through different projects.

Example: Since my initial research experience while a medical student, I have been committed to a career path focusing on patient oriented research. As outlined below, my subsequent experiences have strengthened and refined that initial commitment. As I begin my faculty career, I recognize that I will need additional training in research methodology as well as time protected from clinical activities if I am to fulfill my goal of becoming a successful independent clinical investigator. The additional training and protected research time that would be made available through the K23 award would allow me to further develop the skills required to perform the highest quality patient oriented research in the field of heart failure.

c) ACADEMIC HISTORY : The candidate’s academic background, achievements, educational areas mastered, name of institution, year, universities, research accomplishments and also current academic status.

Example: My research training began in 1991 while a medical student at Duke University School of Medicine. At that time I spent one year of dedicated research time engaged in translational research in the laboratory of S. Clifford Schold, M.D., studying molecular mechanisms of chemotherapy resistance in brain-tumor xenografts. This research experience resulted in two peer-reviewed publications while a medical student1;2 and spurred my interest in making research the primary focus of my medical career. With a goal of obtaining the highest quality clinical training in an environment dedicated to pursuing answers to basic and clinical questions, I pursued my residency training in Internal Medicine at The Johns Hopkins Hospital. After completing my residency training, I was selected to serve as Assistant Chief of Service (Chief Resident) in the Department of Medicine, a rewarding year dedicated to developing as a clinician and educator. During that year I had responsibility for the day-to-day administration of the housestaff training program, and additionally served as the attending physician on the Osler Medical Service for 12 months, admitting and caring for over 1000 hospitalized inpatients. After completing my year as chief resident, I began my cardiology training with a one-year research fellowship at Johns Hopkins under the mentorship of Edward K. Kasper, M.D. and Kenneth L. Baughman, M.D.

d) FOCUS ON CAREER IN RESEARCH: The candidate should give a brief idea of things been planned in future like different courses, projects which will enhance his/her skills and knowledge in the research field.

Example: Because of my desire to change the focus of my career to research, I pursued and accepted my current tenure track position at the University of Minnesota, College of Pharmacy in the Department of Experimental and Clinical Pharmacology. Until this time, my career lacked sufficient time and mentoring opportunities for a dedicated career in clinical research. I selected the University of Minnesota because of its outstanding reputation as a College of Pharmacy, its work in clinical pharmacology, the presence of an internationally recognized Blood and Marrow Transplant Program and the opportunity for focused career development. In the past 3 years, I have begun work in my laboratory, completed three research projects, initiated two clinical research studies and directed and taught portions of hematology, oncology and immunology in Pharmacotherapy Courses in the Doctor of Pharmacy program. I also have developed collaborative relationships with individual investigators within the HSCT Program and Cancer Center.

B] CAREER GOALS: This section should portray the candidate’s goal, that is, what they want to achieve through this grant in near future.

a)GOAL DEFINITION: Goals are the large statements of what you hope to accomplish but usually aren't very measurable. They create the setting for what you are proposing.The section focuses on plans of the candidate to develop academic medical career in respect to patient oriented career research

Example: My long-term career goal is to develop a clinical pharmacology program in hematopoietic stem cell transplantation that will investigate ways to improve immunosuppressive and antineoplastic therapies.

b) HOW GOAL WILL BE ACCOMPLISHED: Here the candidate should jot down the perfect step by step career plan for the accomplishment of goals which makes the plan hard proof.

Example: I will begin to accomplish that goal through the training program outlined and the experience of conducting this research, which will evaluate pharmacokinetics and pharmacodynamics of the immunosuppressant, mycophenolate, in allogeneic nonmyeloablative HSCT.

c) PREVIOUS EXPERIENCE IN SUPPORT OF GOAL: The section highlightens the past experiences the candidate treasures in light of the goals stated. This lays a belief that the goals stated by the candidate have strong valid base.

Example: My previous clinical, didactic and research training have provided me with a solid basis to build a successful research career in clinical pharmacology. I have published research articles in peer-reviewed journals, illustrating my commitment to research. However, my ability to compete successfully for competitive research funding is dependent on obtaining focused research experience and concentrated training.

d) FOCUS ON FUTURE POTENTIAL OF THE GOAL: The benefits and advantages which will be derived by accomplishing these goals are to discussed.

Example: Rapid and ongoing therapeutic development in decompensated heart failure, including both pharmacologic agents and device technologies, will result in multiple potential future avenues of research based on the work outlined in this application. Identification of risk stratification strategies will aid in both appropriate triage of patients and the identification of potential new targets for therapeutic development, such as modulation of the systemic or local inflammatory state.

C] CAREER DEVELOPMENT PLAN

1) IMMEDIATE AND MID-RANGE CAREER OBJECTIVES:

Example: 1. The development of my academic research career requires achieving the following objectives over the next five years: obtaining didactic training in research methodology, acquiring further clinical and outcomes research experience, and successfully preparing grant proposals that prove competitive for peer reviewed funding. In addition, other experiences, such as honing my writing skills, collaborating with basic science investigators, and developing mentoring skills, will be necessary to complement my main objectives.

2. My academic research career development requires achieving the following objectives over the next five years: (1) obtain didactic training in research ethics, fungal pathophysiology, and advanced statistical methods; (2) acquire further clinical and outcomes research experience; (3) obtain preliminary data for future proposals; and (4) write grant proposals that are successful in going through the peer review process and therefore provide funding of my research. In addition, other activities, such as improving my writing skills and learning from senior scientific investigators will be necessary to complement my main objectives.

a) Didactic Training in Research Methodology

b) Clinical Research Training Program

Example: An important component of my career development plan is obtaining formalized didactic training in research methodology. I will accomplish this by completing the Master’s Program in Clinical Research Training at Duke University. This training program provides formalized academic training in the quantitative and methodological principles of clinical research. To date, I have completed the required didactic coursework (24 Master’s level credit hours). To complete the Master’s degree, I will finish my thesis project, which focuses on changes in the population that develops endocarditis.

c) Additional Coursework

Example: To complement the training that I have received through the Master’s program, I will seek additional coursework including logistic modeling with specific emphasis on the use of propensity scores to control for non-random assignment to treatment allocation in observational trials, advanced SAS programming, survival analysis, and randomized trial design. These courses will be taken at the University of North Carolina at Chapel Hill School of Public Health, located 12 miles from Duke.

d) Responsible Conduct Of Research

Example: I have completed six Master’s level credit hours in the Clinical Research Training Program in courses devoted to the responsible and ethical conduct of research (CRP 246, Research Management and CRP 243, Ethical Issues in Clinical Research). In addition, I have completed the modules required by the Duke IRB related to the responsible conduct of research (“Protecting Research Subjects” and “What Counts as Research on Human Subjects?”). Further training will include modules required by the Duke IRB and will take place, at a minimum, on a yearly basis.

2) RESEARCH EXPERIENCE

Example: 1.i. Develop skills in identifying important clinical issues and expertise in designing the appropriate clinical studies to efficiently and effectively answer the clinical questions. ii. Implementation of Research Plan. iii. Develop skills in interpretation and presentation of the results. iv. Develop skills necessary to move from results to the next research question.

2. i.Acquire Skills in Bench Research at the Duke University Mycology Research Unit (DUMRU). ii. Learn and Perform the Diagnostic Tests. iii. Other Projects in the DUMRU. iv. The environment of the Neonatal Network. v.Steering Committee Meetings of the Network. vi.Develop skills in interpretation and presentation of results. vii.Develop experience as principal investigator in the Pediatric Fungal Network (PFN). viii. Develop skills necessary to move from results to interventional trials.

a) MENTORING

i) Mentorship: This section mentions about the main person, who will be guiding the candidate throughout the project

Example: Dr. Ron Goldberg will serve as my primary mentor. As Director of the Duke site of the Neonatal Network, Dr. Goldberg will mentor me in my interpretation of the data and in writing manuscripts that present these results. Under Dr. Goldberg’s mentorship, I will identify, based on the results of this project, promising directions for future research. Dr. Goldberg will also mentor me in future grant writing for ROI funding. Finally, Dr. Goldberg will monitor my progress in the acquisition of “presentation skill set”, such as oral communication of results and written presentation of research. I meet with Dr. Goldberg weekly. We also communicate weekly by phone and by email. This level of communication will continue during this proposal to ensure a successful transition to independent investigator.

ii) Co – Mentor: This section mentions the mentor/s besides the main guide, for additional mentoring throughout the project.

Example: Dr. Kerry Lee will serve as a collaborator on the proposed research and will provide additional mentoring, particularly with regard to methodologic issues and statistical considerations. As senior biostatistician at the DCRI, Dr. Lee has a long record of leadership in patient oriented research at the highest levels, as well as a history of successfully mentoring future leaders in cardiovascular clinical research. He has acted as a statistical collaborator and mentor to many of the DCRI faculty, including DCRI Director Dr. Robert Califf and Dr. O’Connor. Dr. Lee’s mentoring and collaboration will be essential to mastering the relatively sophisticated statistical modeling techniques used in prognostic modeling research. Dr. Lee and I will meet on an as needed basis throughout the duration of this project.

iii) Role of Mentors: This section should explain the detailed direction and guiding role of mentor in this whole grant application at every step to the candidate.

Example: Dr. McGlave has directed me in this preparation of this proposal and is committed to continue to work with me on issues of clinical study design and conduct, immunology of GVHD and donor stem cell engraftment, GVHD assessments, data interpretation and presentation skills. I will meet with Dr. McGlave weekly to review the status of the project and patient accrual, and to discuss GVHD, engraftment and graft vs tumor issues. Dr. McGlave has provided mentorship in the design of the proposed study, grant preparation, committee approvals and will continue to provide senior guidance by assisting in all aspects of the planning, direction and execution of the project. In addition, Dr. McGlave will facilitate collaborations between me and internal and external investigators in HSCT. This will assist me in future projects and collaborations. Dr. McGlave will devote 5% effort per year.

b) ADVISORY COMMITTEE

c) ROLE OF ADVISORY COMMITTEE

d) ANNUAL EVALUATION

3) ADDITIONAL OBJECTIVES:

Example: 1. i. Refine and maintain writing skills. ii. Develop skills and experience necessary to collaborate with basic investigators. iii. Develop Mentoring Skills'

2. Excellence in written communication is part of the “presentation skill set” necessary for a successful, independent research career. I will refine my writing skills in three ways: (1) Writing papers describing the results from the work in this application, (2) Completing the Duke University science-writing course. This intensive course provides instruction in the complexities of producing sophisticated academic arguments, with attention to critical analysis and rhetorical practices,(3) As the initial phases of the Research Plan are completed, analyzed, interpreted and disseminated, I will apply the tools and preliminary data obtained in this proposal to complete proposals for interventional studies in neonatal candidiasis.

4) PEER REVIEW FUNDING:

Example: The expertise of the Outcomes Group and the Grant Development division of the DCRI will be sought to target new funding sources and prepare grant proposals for the continuation of this work. Depending on the proposed project, funding sources may include foundation grants (e.g., Doris Duke Foundation), societal grants (e.g., AHA Grant-In-Aid), or federal sources (e.g., NIH RO1).

5) TIMELINES:

This section should include the 5 year Career Development and Research Plan.

Example: 1. I will devote the first two years of the award to completing additional didactic and bench research training while enrollment is completed for the protocol outlined in the Research Plan (Figure below). I will focus on conducting the assays and developing a risk-stratification model in the third and fourth years of the Award as outlined Research Plan. In the final year of the award, I will publish the results and use the results as a platform to develop new research ideas and pursue funding opportunities for those projects.

6) STATEMENTS BY SPONSOR(S), CONSULTANT(S) AND COLLABORATOR(S)

This section should include :

i. List of Sponsors/Mentors,

ii. List of Consultants,

iii. List of Collaborators,

iv. Letters from supporters.

II] ENVIRONMENT AND INSTITUTIONAL COMMITMENT TO CANDIDATE

1. ENVIRONMENT

GENERAL DESCRIPTION OF RESOURCE

2. INSTITUTIONAL COMMITMENT TO CANDIDATE’s RESEARCH CAREER DEVELOPMENT

III] RESEARCH PLAN

a) GOAL OF RESEARCH: This section should provide an overall understanding of the strength of the project.

Example: The broad goals of the proposed research are to validate existing risk stratification models in patients with decompensated heart failure (DHF), and to evaluate the additive benefit of integrating assessment of inflammatory cytokines into risk stratification strategies.

b) REASON FOR STUDY: This should support the goal and the candidate has to convince the reader as to how essential and importantly necessary his/her goal is.

Example: This proposal aims to address existing knowledge deficits in several key areas: a. Lack of established risk stratification models for patients with DHF. b. Lack of data on inflammatory activation in patients with DHF. c. Lack of understanding of the role of inflammation in the progression of heart failure and the transition from a compensated to a decompensated clinical syndrome. d. Lack of integration of inflammation markers with traditional clinical data in risk stratification. e. Lack of data on changes in inflammatory markers with DHF treatment, and the relation of these changes to the risk of subsequent adverse events.

1. STATEMENT SPECIFIC AIMS AND HYPOTHESIS

Aims: The objective of the study. Objectives are operational, tell specific things you will be accomplishing in your project, and are very measurable.

Example: To prospectively validate the risk prediction models developed through retrospective analysis of the OPTIME-CHF database in a prospective study of patients presenting with DHF.

Hypothesis: A tentative explanation for a scientific problem that can be tested by further investigation should be stated pointwise.

Example: In patients hospitalized with decompensated heart failure, future adverse events can be predicted from baseline data with a clinically useful degree of accuracy.

2. BACKGROUND, SIGNIFICANCE, AND RATIONALE

a) Introduction and background of study: This section should include the statement of the problem to show that the project is definitely needed and should be funded. Previous projects and studies that are similar to the proposed project should be cited to convince the reader that the project is unique since it does not follow the same path as previously followed. Explain briefly why the proposed project is important, innovative, timely, and worth doing.

Example: The combination of the aging of the population and improved survival after acute myocardial infarction has resulted in rapid growth in the number of patients living with chronic heart failure, a trend that will only increase in the upcoming decades.11 With this increase in the prevalence of chronic heart failure has come a concomitant increase in the number of hospitalizations for decompensated heart failure (DHF), defined as a worsening of the signs or symptoms of heart failure of sufficient severity to require hospitalization. DHF now represents the leading cause of hospital admission in the Medicare population in the United States.12 In 1997, 957,000 patients were discharged with a diagnosis of DHF, compared to an estimated 800,000 with acute myocardial infarction.13In addition to its high prevalence, hospitalization for DHF is associated with extraordinarily high morbidity and mortality.In the recently completed OPTIME-CHF study, the largest randomized trial to date in patients with DHF, the 60-day mortality was 9.6% with a rate of combined death or rehospitalization within 60 days of 35.2%14. Rates of rehospitalization among elderly patients with DHF are even greater, with estimates as high as 44% within 6 months15. The combination of high and increasing incidence and substantial morbidity has resulted in a huge burden to the global health care system. Management of heart failure consumes over 19 billion dollars annually in the United States, representing over 10% of the total cardiovascular disease health care expenditures. About 75% of heart failure expenditures in the United States are for hospitalization and inpatient care, indicating that DHF is among the main drivers of cardiovascular health care costs in the U.S.1Despite these facts, therapeutic development and treatment strategies in DHF are lacking, particularly when compared to progress in other diseases (such as acute myocardial infarction) with similar morbidity and mortality.

b) Topic significance: The candidate has to create a scenario with reasoning as to why the topic taken by him/her is important, it should have the convincing power to gain trust of the reader.

Example: Candida species are a leading cause of infectious mortality in the NICU, and the incidence of candidemia in ELBW infants varies from 4-18% (Benjamin 2000, Kaufman 2001, Stoll 2001). Candidemia has an attributable mortality of 20-30% (Stoll 2001). In addition to significant mortality, candidiasis frequently results in severe morbidity. Candida species invade virtually all tissues, including the neonatal retina, brain, heart, lung, liver, spleen, and joints; invasive Candida infections cause blindness, developmental delay, and the need for invasive corrective procedures. (Baley 1981, Benjamin 1999 2003, Chapman 2001, Faix 1984, Faix 1992, Fernandez 2000, Friedman 2000, Karlowicz 2000, Kassner 1981, Mayayo 1996, Miller 1982, Noyola 2001).

c) Information lag: The candidate has to specify as to why he/she selected this topic and what is the main drawback still prevailing In spite of work done previously on it and should explain the uniqueness of the aim.

Example: Neonatal candidiasis related mortality is largely attributable to delays in (or lack of) diagnosis. While the insensitivity of blood cultures in older children and adults has been well documented in autopsy studies, it is not as well documented in neonates.

d) Literature review supporting lag: The facts stated above should be backed with strong, complete, published references which are easily accessible whenever required.

Example:''These are, however, several reasons why culture techniques in the neonate may have as poor, or even worse, performance in neonates:

1) Candidemia is often a disease of low organism burden. The low organism burden is a crucial point given the limitations of blood sampling in neonates (Issacman 1996, Schelonka 1996). In contrast to the 30-60 ml of blood used to diagnose candidiasis in adults, the neonatologist is limited to a blood culture of 1-2 milliliters of blood. Even this amount is substantial for a 500-gram infant whose total blood volume is only 40ml.

2) Because the neonate (like the older neutropenic patient) does not localize infection well, the tropism for multiple tissues seen in older neutropenic patients is also observed in neonates. This means that the neonate is likely infected with Candida in tissues not easily accessible to culture.

3) Finally, not only is blood culture likely to be insensitive, it is slow to provide meaningful results. In a study conducted in neonates, (Garcia-Prats, 2000) 15% of C. albicans isolates from the blood were detected after 72 hours.

3. PRELIMINARY STUDIES AND RESULTS : This section demonstrates candidates relevant experience or preliminary studies conducted or any data from similar projects that support any of the ideas or hypotheses of the proposed goal. Complete references to appropriate publications, manuscripts submitted for review, or manuscripts accepted for publication can be listed in this section.

a) Objective : Example: To identify clinical variables at presentation that would predict the risk of 60-day mortality using multivariate analysis.

b) Outcome : Example: Based on the multivariable model, five clinical variables at presentation were found to independently predict 60-day mortality with a high degree of accuracy (c-index=0.78); age, serum sodium, systolic blood pressure, New York Heart Association class, and blood urea nitrogen (BUN) levels (Table 1).

c) Analysis: Example: Adjusted hazard ratios and 95% confidence intervals for each of these predictors are shown in Figure 1. Internal validation of this model via the bootstrapping method resulted in only minimal bias correction (adjusted c-index=0.76).

d) Interpretation: Example: Although modeling of risk through multivariable regression techniques is statistically powerful, the results are frequently to mathematically complex to be clinical useful in the care of individual patients. Because the 60-day mortality model was able to stratify risk with a high degree of accuracy using a limited number (5) of clinical variables, we converted the multivariable model to a nomogram that would be sufficiently simple for clinical use at the bedside, the Duke Decompensated Heart Failure Risk Score (Appendix 3). If these models are validated prospectively (Specific Aim #1), this type of instrument would be a useful clinical tool in the day-to-day management of patients presenting with DHF.

4. RESEARCH DESIGNS AND METHODS

a) Overview:This section should state the executive summary of the project.Should be specific and concise.

Example:''This work will link promising bench research with clinical outcomes, verify risk factors, test a clinical predictive model, and develop a plan for early diagnosis and presumptive therapy. This work will position the candidate to seek peer-reviewed funding for interventional studies of neonatal candidiasis. This protocol has been approved by the Neonatal Network and will capitalize on the infrastructure of the Neonatal Network and the Duke University Mycology Research Unit (DUMRU).

b) Study design and plan: Studies can be conducted in a number of ways (for example, descriptive, comparative, longitudinal, case-control, quasi-experimental, or randomized) and state why that design was chosen.

Example:''A cohort study design (rather than a case-control study) will be used for the proposed study. This design was chosen because the primary research question relates to the clinical importance of differences in inflammatory markers among patients with DHF, rather than the differences between patients with DHF and controls (elevation of inflammatory markers in patients with advanced heart failure compared to normal controls has already been established).

c) Available resources: All the resources which will be required and management of all the resources. eg Lab, desktops etc.

Example:''1. In order to accomplish the Specific Aims, five specific resources will be used : i. Duke Endocarditis Prospective Cohort Study, ii. ICE Merged Database, iii. ICE Prospective Cohort Study, iv. Collaboration with Dr. Goldschmidt, v. Collaboration with Dr. Fowler.

2. Available resources like Laboratory, Clinical(The clinic consists of 14 examination rooms, a treatment area and 2 consultation rooms), Computer, Office, Others(The University of Minnesota Cancer Center.''

d) Study Population description: The main characteristics of the study subjects with particular reference to medical condition and demographic characteristics.

Example:''1. Our target population consists of NICU patients—infants with birthweight <1000 grams and older than day of life two. Our lower limit of inclusion at day of life two is based on the fact that candidiasis prior to day two is likely to represent a disease process with different pathophysiology and risk factors than nosocomial candidiasis (Melville1996).

2. Adult and pediatric patients with hematologic malignancies, immunodeficiency states or inborn errors of metabolism who are evaluated for nonmyeloablative related or unrelated allogeneic HSCT at the University of Minnesota are potentially eligible for the study'

e) Patient recruitment and enrollment: The candidate should explain the recruitment process(es) and the number of the subjects (sample size) who shall be screened and those who shall be enrolled into the study should be detailed.

Example:''An estimated 100-150 patients/year will be enrolled (300-450 patients over planned 3 year study period). This total represents approximately half of all patients admitted to Duke University Medical Center with a primary diagnosis of DHF. All patients admitted with a primary diagnosis of DHF will be screened for study eligibility within 24 hours of admission.

f) Eligibility: Criteria that must be satisfied by each patient before participating in a clinical trial. Examples include disease type and extent, medical history, and organ system function.

Example: Inclusion criteria: i. An admission diagnosis of DHF as determined by the treating physician, ii. Age > 18 years, iii. Ability and willingness to provide informed consent. Exclusion criteria: i. Cardiac surgery within the previous 30 days, ii. Active infection or other chronic inflammatory conditions (e.g., rheumatoid arthritis, SLE, etc), iii.Active malignancy, iv. Previous cardiac transplantation, v. Severe comorbid illness making 60 day survival unlikely.

g) Study endpoints: A primary or secondary outcome used to judge the effectiveness of a treatment should be defined here in an understandable manner earlier itself.

Example: Two clinically applicable endpoints will be assessed at 60 days—all cause mortality and the composite of all cause mortality or rehospitalization. These endpoints were chosen because they reflect the most clinically relevant risks after hospitalization for heart failure. Although mortality is clearly the most important endpoint in any clinical investigation, rehospitalization represents a major source of morbidity and costs in DHF.

h) Study intervention: The attempted remediation of a health problem. It can be an Observational/non-interventional study (does not involve any active intervention, and is based on observation and recording of events as they occur) or an Experimental/interventional study ( it involves some active intervention - preventive, diagnostic or therapeutic )

Example: Clinical studies (serum albumin and creatinine, total bilirubin, ALT and alkaline phosphatase) will be obtained with pre and posttransplant pharmacokinetic sets and with each weekly trough concentration. Hematology studies will be obtained daily beginning on day 5 posttransplant for assessment of neutrophil engraftment. Daily hematology studies will continue until day 21 or time of stable neutrophil and platelet engraftment. Clinical studies will be obtained regularly until day 100. Blood or bone marrow will be assessed for donor cell engraftment by RFLP analysis as needed. A physical exam will be completed on the day of pre and posttransplant pharmacokinetics and with each weekly trough concentration. Patients undergo physical exams daily in the hospital and after discharge with every visit in the BMT clinic until day 100.

i) Data collection methods: The process of recording the information about each subject during the course of the trial.

Example: A case report form will be developed to collect baseline demographic variables, clinical variables at presentation, major adverse events during hospitalization, specific therapies during hospitalization, laboratory data (including measures of inflammatory markers), and follow-up data.

j) Data management and Analysis: The methods which will be used to analyze the data collected during the study, data storage, data accessibility should be clearly mentioned.

Example: Initially, the data from each site will be combined to determine the proportion (categorical data) or mean value (continuous data) for each variable in the entire database. Comparisons across databases for each specific variable will be made to determine if there are regional variations in patient characteristics. For categorical variables, these comparisons will be made with the χ2 test or Fisher’s exact test where appropriate. For continuous data, these comparisons will be made with analysis of variance (ANOVA) for normally distributed data or the Kruskal-Wallis procedure if a non-parametric test is desirable.

k) Patient follow up: The patient if required will be called back for follow up, need to mention the details .

Example: Clinical follow-up will be obtained via telephone contact or mail contact with all patients 60 days after study enrollment. A dedicated study coordinator with significant experience in conducting heart failure clinical trials will perform all follow-up.

l) Data confidentiality: The importance of the safety of the data collected and how the candidate plans to take steps in that direction is to be detailed.

Example: After data collection on the case report form, data will be entered into a computerized database (Microsoft Access) specifically designed for this study. All patients will be assigned a unique study number to protect data confidentiality. Access to the data will be limited to study investigators, data entry personnel, and statistical programmers and consultants as needed.

5. POTENTIAL PROBLEMS AND LIMITATIONS: A brief discussion of the limitations of the proposed study and alternative methodologies for carrying out the proposed research plan.

Example: Insufficient enrollment/Lower than expected event rate: Successful completion of all specific aims of this proposal is contingent on enrolling a large cohort of patients with DHF. The modeling procedures described in this proposal will require sufficient numbers of endpoints in order to have the required statistical power. Several aspects of the planned study will limit this problem. First, the proposed enrollment of 100-150 patients/year represents less than half of the patients admitted yearly to DUMC with a primary diagnosis of heart failure (approximately 300-400/yr). Secondly, our estimates of event rates are conservative, since they are based on the patient cohort from a randomized clinical trial (OPTIME-CHF) that tended to exclude very high-risk patients. In the event that enrollment at a single center does not appear sufficient to achieve the needed statistical power, enrollment could be expanded by screening patients at the Durham Veterans Administration Medical Center (DVAMC), immediately adjacent to DUMC. DVAMC admits an additional 50-100 patients year with a primary diagnosis of DHF, and thus could serve to increase the available patient population with a relatively small increase in study resources.

6. FUTURE DIRECTION

Example: The successful completion of the proposed specific aims will open multiple avenues for future investigations. If inflammatory activation is shown to be associated with adverse outcomes in DHF patients, then a logical next step will be randomized clinical trials of anti-inflammatory therapy in DHF patients with inflammatory marker elevation. The risk prediction models developed through this proposal would play an important role in identifying high risk patients for such a study, as well as in other trials of novel therapies in DHF.

7. HUMAN SUBJECTS

a) Human subjects: The U.S. Department of Health and Human Services, which encompasses the National Institutes of Health (NIH), regulates the treatment of human subjects through a set of internationally recognized ethical principles. These principles are designed to safeguard a research participant's rights and welfare. These regulations are contained in a document called [45 CFR 46-Protection of Human Subjects] . Candidate must provide specified information regarding human subjects in their funding applications and also detailing how you will protect the study participants.

b) Gender, minorities and children: Gender and minority representation must be discussed, and a justification provided if adequate representation is not applicable or not possible.

8. VERTEBRATE ANIMALS The vertebrate animals section is the equivalent of the human subjects section for a scientist who uses laboratory animals in the course of his or her research. This section describes how you will treat your laboratory animals ethically and humanely.

IV] LITERATURE CITED

V] CONSORTIUM ARRANGEMENTS

VI] APPENDIX Information placed in appendices should be completely nonessential and supplemental.