GEMS Grants Writing

1. GEMS Grants Writing D.C. Rao • Basics & Various Steps • Research Plan: Review Structure & Format • Designing Family/Genetic Studies & Consent Issues; Types of Grants; Assignment • Human Subjects Issues & IRB; Revising a Grant • Review Assignments in Class ACKNOWLEDGMENTS Kelle H. Moley, MD; Dept of OB/GYN Linda Pike, Ph.D.; Dept of Biochem & Mol Biophysics

2. Grant Writing I. Basics & All the Steps Involved in Grant Writing Conceive an innovative idea And testable hypothesis Evaluate feasibility & reality If not funded the first time, consider revision and re-submission; learn how to revise Carry out literature review effectively & responsively And prepare the background Generate preliminary data Revise as necessary & submit to the funding agency Prepare the grant application keeping An appropriate funding agency & study It often helps to have it critiqued Section in mind By a couple of experienced investigators

3. Grant Writing: Some Facts In general, better grants get funded but not all good grants are funded; sometimes not-so- good ones also get funded! Learning to write a good grant is a life long learning experience; there are no short cuts! These days, NIH grants are rarely funded upon the 1st time; successful grants are usually funded upon 2 revisions There is no safe, reliable, and dependable method; the same approach works sometimes but not always!

4. Grant Writing: Some Facts Funding of a grant depends on several factors not all of which are under the PI’s control Well written grant Composition of the particular Study section, the specific reviewers of your grant What are you willing to do to maximize the chances of funding? Submission of a grant does not guarantee funding, but not submitting a grant guarantees no funding! Also, submission of a bad grant guarantees rejection!

5. Components of a Good GrantThese are necessary, but can not guarantee success Sound, creative and innovative idea & a testable hypothesis Determination and commitment to make it work; translate determination into action! Explore the feasibility & discuss with experienced colleagues Generate pilot data/ preliminary studies Articulate the idea into an attractively written grant Seek frank critiques from experienced colleagues and improve the presentation prior to submission Never submit a grant too soon. Since successful NIH grants usually take a total of 3 submissions, it is some times tempting to start early knowing that anyway it will take 3 submissions. Avoid such temptation since most of the 2nd submissions are NOT funded! You have just 3 chances to make it work, and make good use of every opportunity you have!

6. Grant WritingIssues to Consider • How to write a good grant? • Feasible, realistic, and timely • How to select a Funding Agency (say, NIH), Institute within the NIH, and a Study Section? • How to revise a grant in a responsive and effective manner?

7. Grant Writing: Complete Package • Title page • Abstract page and Key personnel • Contents page • Budgets & Budget justification • Biographical Sketches with Other Support • Resources & Environment • Research Plan (A, B, C, D) • Human Studies • Inclusion of Women and Minorities • Inclusion of Children • Vertebrate Animals • Consortium/Contractual Arrangements • Letters of Support • Data/Resource Sharing Plan • Appendix • Literature Cited

8. Research Plan: Contents for Planning • SPECIFIC AIMS • BACKGROUND AND SIGNIFICANCE • Limitations and Critical Barriers to Gene Discovery • Modulation of genetic effects by age • Modulation of genetic effects by obesity • Metabolic and CVD risk factors as a Major Public Health Problem • Uniqueness and Significance of the Proposed Study • PRELIMINARY STUDIES • Experience of the Investigators in Genetic Epidemiology Research • The GenSalt Family Study • Preliminary results on exploring the new direction to gene discovery • RESEARCH DESIGN AND METHODS • Brief Overview and Rationale of the Research Plan • Characteristics of the GenSalt Study Participants • Methods for Specific Aim 1 • Definition of Primary and Secondary Phenotypes • Variance Components Linkage Analysis Methods • Gene-Age Interactions in Linkage Analysis • Statistical Power • Anticipated findings, future studies, and potential problems/ resolutions • Methods for Specific Aim 2 • Definition of Phenotypes • Gene-Obesity Interactions in Linkage Analysis • Statistical Power • Multiple Testing • Potential Limitations and Backup Plans • Timeline • Protection of Human Subjects • Inclusion of Women & Minorities • Inclusion of Children • Vertebrate Animals • Consortium/Contractual Arrangements • Letters of Support • Resource Sharing Plan • Appendix • Bibliography

9. Grant WritingII. Research Plan: Review Structure & Format D.C. Rao Division of Biostatistics Washington University in St. Louis School of Medicine ACKNOWLEDGMENTS Kelle H. Moley, MD; Dept of OB/GYN Linda Pike, Ph.D.; Dept of Biochem & Mol Biophysics

10. Research Plan Up to 25 pages depending on the type of grant R21: 15 pages R21 does not require “Preliminary Studies”, however, it would be desirable to include some preliminary data and justify that the proposed work is feasible! R01: 25 pages Requires convincing “Preliminary Studies” and some publications and/or abstracts. When planning for an R01, it is generally advisable to generate limited preliminary data first and then apply for an R21 for generating the necessary preliminary studies for subsequently preparing the R01 application. NIH-acceptable format for preparing grant applications include: Arial font 11, single space, with ½ inch margins all around

11. Specific Aims: Generally one page Lead Paragraph: Rationale and motivation: Set the general background with a dramatic but factual opening, e.g.: “High dietary sodium and low potassium intake are associated with increased blood pressure (BP) in observational studies. Dietary sodium reduction and potassium supplementation lower BP in randomized trials, although the BP reduction varies among individuals. The relationship between sodium and Potassium sensitivity and risk of hypertension has not been well studied”. “Despite major advances in the control and treatment of Coronary Heart Disease (CHD), CHD continues to be a major cause of mortality in the US and throughout the world, constituting a serious public health challenge”. • Identify gaps in the knowledgebase Second Paragraph: Objective and Proposed Study The objective of the proposed study is to investigate and characterize the relationship between sodium and potassium sensitivity and risk of hypertension. ……………. Toward this objective, we propose the following specific aims:

12. Specific Aims: Generally one page (continued) Specific Aim 1:To determine ….. Specific Aim 2:To evaluate …. Usually 2 to 4 Aims (hypotheses may be stated as part of each Aim Specific Aim: Investigate the degree to which obesity modulates the genetic effect on cardiovascular and metabolic risk factors, with particular emphasis on risk factors related to insulin resistance and blood pressure, by incorporating gene-obesity interactions as part of the analysis method. Hypothesis: Obesity modulates genetic effects on cardiovascular and metabolic risk factors. Concluding (Salesmanship) Paragraph: Innovation & Expected Benefits:Recall the novelty, innovation, and the potential benefits: “Upon completion of this work, we expect to learn …Thus, these findings are ultimately expected to have a significant impact on the filed of ….”. “This study is expected to make a significant contribution to the understanding of how ..”. “We anticipate that the findings of this exploratory study (R21) have the potential to open up new avenues of research relating to the discovery of the genetic architecture underlying common complex traits ….”

13. Background & SignificanceGenerally 2-3 pages Lead Paragraph: Provide an attractive opening paragraph to Background • Review literature, identifying significant and critical gaps in knowledge • Relate the gaps to your specific aims, reiterating the importance of the proposed research. • Organize into multiple sub-sections Conclude with a “Significance” Paragraph:Stress why this study is important to conduct, what the significant benefits would be if this is performed, and what are the negative consequences if it is not conducted!

14. Preliminary Studies (Progress Report)Generally Up to 8 pages It is a good place to emphasize the expertise, experience, and the unique strengths of the investigative team (which may not be clear from the Bio’s or the preliminary studies! • Also describe any special circumstances pertaining to this study which may not otherwise be clear. • Describe all relevant preliminary studies: • Avoid discussing results which are not very relevant • More is not better, relevance is important

15. Research Design & Methods • Provide an “Overview” section describing in broad strokes your overall research strategy • Organize all methodological detail for each Aim into separate sections • Sample/Assays/Experiments etc • Data Generated • Statistical Methods of Analysis • Statistical Power for testing each hypothesis • Desirable to include a section devoted to “Anticipated findings, future (follow up) studies, and potential problems and resolutions”. Alternatively, such a section may be added after all the methods for all the aims, and address the issues globally. • Various grant formats have additional requirements (which may not be considered against the page budget) (e.g., Data Sharing, Resource Sharing, Multiple PIs etc)

16. Grant WritingIII. Designing Family/Genetic Studies & Consent Issues; Types of Grants; Assignment D.C. Rao Division of Biostatistics Washington University in St. Louis School of Medicine ACKNOWLEDGMENTS Kelle H. Moley, MD; Dept of OB/GYN Linda Pike, Ph.D.; Dept of Biochem & Mol Biophysics

17. Designing a “Genetic Study” Family study or Population study? Choice must be justifiable Recruitment and Informed consent issues are different for the two types of study Population Genetic Study: Each individual (potential) participant is contacted independently of all other (potential) participants, and each one gives informed consent for himself/herself Family Study: We should first target a certain individual (propositus, proband etc, who satisfies certain inclusion/ exclusion criteria; e.g., un-medicated hypertensive with age at diagnosis below 55 years of age) and seek his/her consent for participation in the study, and also seek his/her assistance & consent for contacting other specific types of family members (eg, spouse and children, all sibs and parents etc). Recruitment criteria for families can be more complex and challenging. How to ensure that families with at least 2 sibs (say) will actually participate in the clinical/genetic study? Handling biological materials (like DNA) & genetic information (like marker data) requires special attention

18. Does the study involve Human Subjects? Level of Informed Consent Keep in mind that sharing of data and biological materials with investigators outside your immediate study requires appropriate level of consent. Examples of levels of consent for a hypertension study: Very restricted: Data and biological materials may be used by the study investigators exclusively for the purposes of the study at hand. Limited access to outside investigators: Data and biological materials may be used for hypertension and cardiovascular research in general. Unrestricted: Data and biological materials may be used for biomedical research to improve human health. Protect confidentiality of the data and never violate the informed consent

19. Patients' Data on Stolen Laptop: Identity Fraud Not Likely, NIH Says By Ellen Nakashima and Rick Weiss, Washington Post Staff Writers Monday,March 24, 2008; A01 • A government laptop computer containing sensitive medical information on 2,500 patients enrolled in a NIH study was stolen in February, potentially exposing seven years' worth of clinical trial data, including names, medical diagnoses and details of the patients' heart scans. The information was not encrypted, in violation of the government's data-security policy. • The incident is the latest in a number of failures by government employees to properly secure personal information. This month, the Government Accountability Office found that at least 19 of 24 agencies reviewed had experienced at least one breach that could expose people's personal information to identity theft. • NIH officials said the laptop was taken Feb. 23 from the locked trunk of a car driven by an NHLBI laboratory chief named Andrew Arai, who had taken his daughter to a swim meet in Montgomery County. They called it a random theft. Arai oversees the institute's research program on cardiac magnetic resonance imaging and signed the letters to those whose data was exposed. • In the letter, Arai told the patients that "some personally identifiable information" was on the stolen computer, including names, birth dates, hospital medical record numbers and MRI information reports, such as measurements and diagnoses. Social Security numbers, phone numbers, addresses and financial information were not on the laptop, officials said. • Arai's letter said that the NIH Center for Information Technology determined that the theft posed "a low likelihood of identity fraud" or financial harm. "It is, however, an unfortunate breach of our commitment to protect the confidentiality of your research records," he wrote.

20. Assignment • Select one of the two actual grants provided, critique it thoroughly, with particular emphasis on Specific Aims and Methods. • Prepare a one page written “Summary Statement” by evaluating the grant application, and submit the day before the presentations are due (item 3 below): • One paragraph summary of the grant proposal • One paragraph summarizing the strengths of the proposal • One paragraph summarizing the weaknesses of the proposal • Present your review in class in 3 minutes at the time of our last session (you may do this with or without slides; only 3 slides allowed) • Page limits and time limits will be strictly enforced!

21. Types of Grants • Investigator Initiated Research Grants: • R03 Limited data analysis grants • R21 Two year exploratory grants for generating pilot data for R01’s • R01 Fully mature investigations • Career Development Awards: • K-Awards of several types (handout)

24. Types of K-Awards by NHLBI

25. Grant WritingIV. Revising a Grant, Discussion of Specific Aims prepared for the other course, and Open Discussion about Designing Genetic Studies D.C. Rao Division of Biostatistics Washington University in St. Louis School of Medicine ACKNOWLEDGMENTS Kelle H. Moley, MD; Dept of OB/GYN Linda Pike, Ph.D.; Dept of Biochem & Mol Biophysics

26. Grant WritingThings to Consider When Revising a Grant Application Read the summary statement carefully (and “walk away from it for a few days”, but stay focused!) Read it again and compile all criticisms into one list of “Significant Concerns”, grouping them as necessary. All relatively minor concerns my be grouped into “Other miscellaneous concerns”). Make a prioritized list of the major criticisms (usually 2 to 5) & prepare a response plan for each of them. Some of them may require additional pilot/preliminary data or simulations. Avoid the temptation of re-submitting the revision for the immediately available dead line; inadequate revision and premature re-submission can and often does backfire, faring even worse than before (thus wasting one of 2 or 3 windows of opportunity) Patience is a virtue but procrastination is not!

27. Grant WritingThings to Consider When Revising a Grant Application # 2 Open Discussion about Designing Genetic Studies, and Remember, the reviewers are also expert scientists like you and me. While your anger at the reviewers’ disapproval of your grant is understandable, avoid directing your anger at the reviewers It would be more productive for you to assume that you have failed to present your grant in a convincing and compelling manner. Remember, most submitted grants are good. Yours has to be at the top of good grants! Therefore, simply revising a grant rapidly based on the criticisms may not be enough to secure funding. Take advantage of every opportunity you have for continuing to improve the grant. Remember, reviewers have no obligation to us but they work hard for us, so be gentle and make them feel appreciated (“Inspired by the cogent comments of the reviewers, we have undertaken an extensive revision”). Reviewers are also human and some times they do make mistakes (especially if our grants are not well written to start with). Avoid the temptation to use offensive language (preferable to say “we respectfully submit that ….”). Prepare the best possible INTRODUCTION section (up to 3 pages). For revised applications, if this section has not convinced the reviewer, may be nothing else is going to! Be very well organized, clear, and succinct. Salesmanship is key!

28. Grant Writing • Presentation & Discussion of Specific Aims • Discussion about Design of Genetic Studies • Discussion about the Assignment • Next Session: Assignments due (written & oral presentations

29. Grant WritingV. Last Session Assignments due (written & oral presentations