國科會計畫撰寫實務 吳明賢 台大醫院內科部主治醫師 台大醫學院一般醫學科教授 Publish or Perish Why Individuals Write Grants • Career development & progression • Personal objectives • Employer or other expectations • Fame and financial rewards 知彼知己,百戰不殆 孫子兵法謀攻篇 Background Information on Grants • Type of grants • Funding sources • Understand the reviewer’s perspective Type of Grants • Project vs. Career development grants • Basic vs. Clinical Research • Hypothesis-driven vs. Hypothesis-generating research Four Major Types of Funding Source • Government 政府 • Private foundations 私人基金會 • Industry 藥廠 • Philanthropic 慈善團體 Why National Science Council • More prestigious than others and obtaining these types of grants may be more important for your career whether judged by you or your peers • Current approval rate: variable, depending on PI, institution, type of grants etc. Anesthesiology 1988; 88:1660-6 Successful Grant Applications • Critical to success in academic society • Both ends of the process: writing & reviewing 慎始(壹) • 先上國科會生物處網頁及最新消息公告事項或 特別規劃之公開徵求計畫案件 • 參加國科會業務及計畫撰寫說明暨座談會 • 國科會生物處長給學界的信要詳讀 • 確定所用的計畫書是最新版本 慎始(貳) • 參考過去成功得到經費的研究案子(Review Successful Grant Applications) • 尋求資深或有經驗人員的意見(Get Advice and Input from Mentor or Senior Investigator) • 了解你的reviewer (Know your Audience) 國科會計畫審查作業 • 由二位專家初審評分並給予意見(計畫本身60%及研 究者過去表現40%) • 由二位複審委員根據初審意見再予以評分 • 學門召集人召開複審會議決定通過標準 • 最後通過經費及案子由各學門召集人會議共同決定 Stamp of Approval • Significance • Approach • Innovation • Investigator • Environment Science 1997; 278(5314):888-9 SIGNIFICANCE • Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? APPROACH • Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? INNOVATION • Does the project employ novel concepts, approaches, or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? INVESTIGATOR • Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? ENVIRONMENT • Does the scientific environment in which the 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? Major Review Issues in National Institutes of Health Grant Proposals (n=66) Area* Grants,n (%) Specific aims/hypothesis 30 (45) Goals overstated, overly ambitious or unrealistic 12 (18) Poorly focused or inadequately conceptualized 10 (15) Hypotheses not clearly articulated 8 (12) Inouye Sk et al. Ann Intern Med 2005; 142:274-82 Major Review Issues in National Institutes of Health Grant Proposals (n=66) Area* Grants,n (%) Background/significance Need for study not well justified Too much background, insufficient room for methods, 24 (36) 19 (29) 3 (5) extraneous information Overstatement of significance of study 2 (3) Major Review Issues in National Institutes of Health Grant Proposals (n=66) Area* Preliminary/pilot studies More pilot work needed Grants,n (%) 33 (50) 27 (41) Studies cited with no clear link to proposed study 4 (6) Inadequate description of preliminary studies 2 (3) Major Review Issues in National Institutes of Health Grant Proposals (n=66) Area* General issues Grants,n (%) 24 (36) Layout poor (editing/typographical/grammatical errors, 13 (20) inconsistencies, too-small font, omitted lines or tables, poor photocopy, difficult to read) Use of jargon, abbreviations, undefined terms 3 (5) Information presented in wrong sections 3 (5) Limitations not adequately discussed 2 (3) (For revision) Inadequately responsive to previous 5 (8) reviewers’ comments Major Review Issues in National Institutes of Health Grant Proposals (n=66) Area* Methods Generally underdeveloped Study sample Inclusion criteria Flawed sample (nonrepresentative, potential bias) Poorly described Exclusion criteria Reasons for exclusion not well justified Grants,n (%) 66 (100) 10 (15) 46 (70) 36 (54) 24 (36) 12 (18) 23 (35) 12 (18) Important exclusions overlooked Postenrollment exclusions (potential bias) 7 (11) 4 (6) Availability of study participants not assured 4 (6) Major Review Issues in National Institutes of Health Grant Proposals (n=66) Area* Grants,n (%) Data collection/procedures 18 (27) Inadequate description of study instruments or variables 9 (14) Concerns about validity or reliability of data collection methods 5 (8) Important variables omitted 2 (3) Many study variables not used in analyses 2 (3) Outcome Concerns about adequate blinding of outcome assessment 40 (66) 24 (36) Outcome measure inadequately described, defined, or specified 15 (23) Concerns about validity or reliability of outcome measure 9 (14) Major Review Issues in National Institutes of Health Grant Proposals (n=66) Area* Intervention Inadequate description of how adherence will be monitored or analyzed Method of randomization not described or potential bias in selection process Concerns about potency of intervention Poorly described or unstandardized protocol Unblinded administration of intervention Concerns about unaddressed safety issues Controls Issue of contamination or co-intervention Lack of or inadequate description of control group Grants,n (%) 16 (24) 9 (14) 5 (8) 5 (8) 4 (6) 2 (3) 2 (3) 7 (11) 4 (6) 3 (5) Major Review Issues in National Institutes of Health Grant Proposals (n=66) Area* Grants,n (%) Data analysis 42 (66) Inadequate control for important confounders 21 (32) Insufficient description of analytic approach 16 (24) Intention-to-treat analytic strategy needed 7 (11) Inadequate description of handling missing data or nonresponses 7 (11) Sample size/power 28 (42) Lack of or inadequate description of sample size or power 17 (26) calculations Estimates of attrition rates not provided, too low, or require 13 (20) justification Anticipated attrition or losses to follow-up that threaten 2 (3) validity of study Things to Think About Before You Start to Write Your Proposal (I) • What is to be done? What is the hypothesis to be tested or question to be answered? Is it easy to collect new data or repeat experiments in the new system. What is the rationale for your project? What is novel/unique about the idea/concept? • If the work is original (and, even more so, if it isn’t), why is it worth doing (significance)? • What are the specific objectives? What is the long-range goal? • Is the methodology ‘state of the art’? Things to Think About Before You Start to Write Your Proposal (II) • Who will do the work (the reputation of the grantee and her/his team)? • Why should they let you do it? What are your unique qualifications? • How long will the work take? Have you formulated a realistic timetable? • How much will it cost (budget) and why (budget justification)? • What other funds are – or might be – available to support the project? • How will the project be supported in the future after the requested funding is used up? Things to Think About Before You Start to Write Your Proposal (III) • Where will the work be carried out? • What facilities will the work require? Do you have access to such facilities? • How will the project benefit the granting institution? • How will the project benefit the advancement of science and the work of other scientists? • How will the project benefit society (health-relatedness)? Things to Think About Before You Start to Write Your Proposal (IV) • For corporation grants: How will the project increase the wealth and/or stature of the corporation? • What are the expected results, and what are your contingency plans if you hit a snag? • Are you and your team aware of what has been done in this and related fields (background)? • Does the agency require a pre-application or letter of inquiry? STEPS FOR CREATING A GOOD GRANT PROPOSAL (I) • Research topic • Formulate ideas/hypotheses for proposal • Plan project • Do preliminary studies • Make an outline of the proposal • Revise outline until all necessary information is included and all is in a logical order STEPS FOR CREATING A GOOD GRANT PROPOSAL (II) • Convert outline to prose document • Proofread and revise document (proposal) • Send to three readers to evaluate content (accuracy), clarity, consistency, brevity and style (emphasis, tone, presentation) • Incorporate appropriate suggestions from readers • Do final revisions, proofread, finalize proposal Minimum timeline for funding of a “perfect” grant application to the National Institutes of Health J Pediatric Gastro & Nutr 2002; 35:107-10 “The important thing is not to stop questioning” “I have no particular talent, I am merely inquisitive” 研究題目之選擇 • 地區性vs.世界性問題 • 方向性觀念vs.跨域觀念 • 基礎vs.臨床 Research Proposal Team of Excellence Research Program (This form is for main project and all sub-projects) Ⅰ. General Information Title of Main-project Title of Sub-project Application Number: Exploring the role of inflammation and immune reaction in mediating English Helicobacter pylori-independent transformation of gastric mucosa-associated and lymphoid tissue lymphoma Chinese 發炎與免疫反應在幽門桿菌非依存在性胃黏膜相關淋巴組織淋巴瘤轉型 的角色 Determination of the relationship between polymorphisms in inflammation English and immune regulation genes and various tumor response of gastric mucosa-associated lymphoid tissue lymphoma to H. pylori eradication and therapy Chinese 探討發炎與免疫相關基因多形性與幽門桿菌治療後胃黏膜相關淋巴組織淋 巴瘤各種不同腫瘤緩解反應的闗係 English Name of Principle(Chief) Investigator* Chinese Ming-Shiang Wu Institution/Department Department of Internal Medicine, College of Medicine, National Taiwan University Project Period Position 吳明賢 Associate Professor 2006 - 2008 Does this research project involve the following? (Check and attach relevant consent forms, if applicable.) Human Studies Gene Modification Animal Studies Name: Corresponding Person (Chinese) 吳明賢 (English) Ming-Shiang Wu Mailing Address in Chinese: 台北市中山南路 7 號 Telephone: (Office)2312-3456ext5410 Fax: 2394-7899 (Home)2727-5866 (Mobile)0968661025 E-mail: stanley@ha.mc.ntu.edu.tw Principal Investigators’ Affidavit: The research proposed in this grant application has not been financially supported by any funding agency. Any recent research projects and submitted proposals are listed in Form CC13. I am aware that any withholding, falsification, or misrepresentation of information could result in administrative actions such as the dismissal of an application or the suspension and/or termination of an award, as well as other possible punitive actions. Signatures -- Principle(Chief)Investigator: Date:________________ 創新 • 等於借用加連結 • 前提是必須知道別人做了什麼 • 畢卡索(Picasso):好的藝術家懂複製。偉大的 藝術家則擅偷取 • If you steal from one person, that’s plagiarism. If you steal from ten, that’s research. If you steal from 100, you are a professor. 摘要(Abstract) • 永遠的第一印象(everlasting first impression) • 很多reviewer只看摘要,因此務必精要但令人想看 • 必須包括hypothesis/specific aim/methodology/significance 好的摘要 • 可從研究者實驗室long-term goal和本次計畫的 current goal寫起 • 依序為biologic/biomedical significance, central hypothesis that guide the entire research, the 25(一般為3個)specific aims, experimental design/methods, desirable outcomes of the research proposed • 若能簡短提出研究結果對目前領域的影響及衝擊做 結尾將更完美 Background and significance: Although Helicobacter pylori (HP) is present in the vast majority of MALToma, only small subsets of infected individuals develop this malignancy, suggesting other factors must be involved in determining the fate after exposure to HP. Furthermore, eradication of HP by antibiotics induces durable tumor remission in 60-70% of patients, indicating existence of HP-independent mechanisms of transformation. Recently, we have found that some HP-dependent gastric MALToma may persist for a long time, even up to two years after HP eradication, before it eventually remits. It is conceivable that some of those delayed responders may have been classified as HP-independence and unnecessary modalities of treatment such as surgery, chemotherapy and radiotherapy may be given. Therefore, identification of determining factors associated with HP-dependent and –independent transformation and the variable treatment response is crucial not only for a better understanding of the pathogenesis of gastric MALToma but also for future prevention and treatment of this special malignancy. It was assumed that the deregulation between The HP infection and the host’s immune response is essential for pathogenesis and responsible for the various outcomes after H. pylori infection. Accordingly, factors involved in the initiation and regulation of the inflammatory response would dictate the disease outcomes. Inappropriately regulated inflammation of the gastric mucosa is orchestrated by sequential elaboration of pro-inflammatory cytokine and the in vitro maximal capacity to produce different cytokines varies among different individuals. Such individual differences are genetically determined and can be attributed to several molecular mechanisms, including single nucleotide polymorphisms in the coding or promoter regions of cytokine or cytokine receptor genes. These polymorphisms may affect the overall expression and secretion of cytokines. The observed genetically determined differences in inflammatory response might thus account for some of the heterogeneity of infectious diseases. However, most studies in this context focus on susceptibility rather than HP dependence and studies centering on correlation of genetic polymorphisms with HP-dependent status and other genetic changes remain lacking. polymorphisms with HP-dependent status and other genetic changes remain lacking. Specific aims: To identify potential biomarkers and genetic determined differences in inflammatory and immune responses that are associated with various tumor response of gastric MALToma to HP eradication therapy. Patients & Methods: We will enroll cases with various responses (immediate, delayed, or non-responder) to HP eradication therapy and healthy controls to collect genomic DNAs and bacterial strains. Candidate inflammation and immune regulation genes with functional polymorphisms will be selected from published data as well as the aid of subproject 1 or 4. Correlation of gene polymorphisms with HP-dependent status, pathological staging, clinical outcomes and different genomic changes (subproject 4) will be performed. Moreover, we will in vitro investigate the biological significance of potential gene polymorphisms with statistical significance under the help of subproject 1&3. Expected contribution: This study will elucidate the independent or interactive effects of genetic variations in mediating the various tumor response of gastric MALToma and provide a more in-depth picture of MALTomagenesis by including the role of genetic differences. Keywords: single nucleotide polymorphism, clinical outcome, mucosa-associated lymphoid tissue lymphoma 中心假設(Central Hypothesis) • 必須可以驗證(testable)或回答(answerable) • 最好是嶄新(novel)且以現在和主動語氣(present tense and active voice)陳述 • 若能分成幾部分,每部分由-specific aims驗證則 更佳 HP-dependent MALToma Autocrine TNF-a/BAFF Follicular dendriticcells T-Cell Delayed Responder MALToma HP-independent MALToma 研究目標(Specific Aims) • 在簡介(通常一段文字)及假設之後帶出研究目標 • 通常可以列出2-5個目標,一般計畫常見為列出3個 • 目標彼此雖有相關,但最好是獨立可驗證,以避免 第一個(或第一年)目標無法達成,則往下的目標也 無法進行 SPECIFIC AIMS (Example) Based on previous studies and our preliminary results, the current research project aims to: 1. Determine alterations of plasma levels of ghrelin and leptin in patients undergoing different bariatric surgery and to investigate possible correlations between these levels and various factors, such as weight loss outcomes, H. pylori infection and duration of surgery. 2. Clarify whether different forms of circulating ghrelin are related to H. pylori infection and postoperative weight loss outcomes. 背景(Background)和意義(Significance) • 簡要(約1/4篇幅)但明白清楚的介紹此研究目的,根據文獻 目前此領域已知和未知的部分,這些未知或不清楚部分在 此研究達成後,是否可得到解決 • 以簡圖介紹過去模式及本研究提出的模式更能讓reviewer 了解此研究之創新性 • 若能符合邏輯地描述此研究計畫為過去的延伸,並且能提 供新知識則更理想 • 謹慎使用初步結果並且引用可能reviewer所發表過的文獻 初步資料(Preliminary Data) • 主要目的在讓reviewer相信主持人有能力執行所提 出的研究計畫 • 好的初步成果可支持主持人所提出的創新假設 • 也可以圖表陳述 • 若能有系統地配合specific aims表示則更佳 • 整體而言約佔1/4~1/3篇幅 PRELIMINARY STUDIES (Example) (1) Effects of obesity surgery on the metabolic syndrome (Arch Surg 2004; 139:1088-92). In this study, we have documented that metabolic syndrome is prevalent in 52.2% of morbidly obese individuals enrolling in an obese surgery program. Significant weight reduction 1 year after surgery markedly improved all aspects of the metabolic syndrome and resulted in a cure rate of 95.6%. Obesity surgery performed by laparoscopic surgery is recommended. In addition, we have enrolled a cohort of patients who have undergone different types of bariatric surgery. (2)The influence of H. pylori infection and corpus gastritis on the postoperative outcomes of laparoscopic vertical banded gastroplasty (Obes Surg, in press) In this prospective cohort of 152 patients, we have demonstrated H. pylori infection and gastric inflammation play a significant role in the amount of weight loss after laparoscopic vertical banded gastroplasty. However, we did not provide relevant data regarding ghrelin and leptin levels in this study. Further prospective studies should examine possible mechanisms and long-term effects on weight loss. Cum ula t ive Prob a bilit y of Co m ple t e Pa t holo gic Re m is s ion 1.0 High-grade .8 Low-grade .6 .4 Grade N Low 24 High 14 .2 median time to CR (95% CI) 6.60 (1.40 Š 11.8) months 4.03 (2.38 Š 5.68) months 0.0 0 3 6 9 12 15 18 21 24 27 30 Tim e a ft e r Hp Era d ica t io n (m o n t hs ) Figure 1. Time remissionafter af terHp Hp eradication therapy Timeto to complete complete pathologic remission eradication therapy in in patien with Hp-dependent low-grade and high-grade ly mphoma. patients with Hp-dependent low-gradeMALT and high-grade MALT lymphoma 方法(Methods)-(壹) • 是研究計畫的精華(約佔1/3~1/2篇幅),但很多研究者寫計畫到 此部分已精疲力竭 • 假設reviewer中有一人是此方面專家,因此所用的方法要stateof-the-art • 最好有系統地配合preliminary data和specific aims陳述,例如 D1 methods,相對於C1 preliminary data和A1 specific aim • 若能以不同角度的方法來回答同一問題,則更好 • 即使再好的方法也可能有弱點及限制,誠實陳述並提出有創意 的解決方法,更能博取reviewer信任 • 附上實驗進行進度及時程表(time line) 方法(Methods)-(貳) • 臨床研究計畫必須對study design, conduct和 analysis等仔細描述 • 常見的study design錯誤包括(甲)primary outcome 沒有言明(乙)沒有randomization或blinding(丙)對 sample size大小沒有說明(丁)沒有調整因dropout refusal的病人總數(戊)藥物試驗只有single dose沒 有考慮dose-response 方法(Methods)-(參) • 常見的試驗進行錯誤包括(甲)缺乏對藥物濃度的驗証(乙)最後結果未能 適當重現(inadequate reproducibility)(丙)缺乏對procedure的標準化(丁) 病人追踨不完整(戊)資料記錄不完整(己)缺乏整體性的組織架構 • 常見的統計錯誤包括(甲)沒有預估樣本數和power(乙)將連續變數視為 類別變數分析(丙)須要用較完整的modeling時反而用repeated t tests(丁)數據非常態分佈時仍以此假設分析(戊)缺乏covariate effects的 考量(己)無法區別inter-individual及intra-individual的差異 • 最好有生物統計專家協助,而不要在方法上寫”appropriate statistical methodology will be used or by nonspecific statistical jargon” Checklist for the Grant-Writing Process (I) Section and Topic Questions To Address Specific aims/hypotheses Are the aims well focused and fully conceptualized? Are the hypotheses clearly articulated? Do the aims appear balanced—not overly ambitious or unrealistic? Is the significance/importance of the work evident? Is the work innovative? Does it contribute substantially to previous work in the field? Is the need for the study (or all aspects of the study) well-justified? Is the significance overstated? Is there extraneous information? Are preliminary studies well described and their contributions to the proposed project clear? Is there sufficient pilot work? Is availability of subjects assured? Are enrollment and/or intervention procedures tested and feasible? Background/significance Preliminary/pilot studies Checklist for the Grant-Writing Process (II) Section and Topic Questions To Address Methods Study sample Are inclusion and exclusion criteria fully described and well-justified? Are the reasons for selecting this sample clear, not merely convenience? Are there important potential biases in the sample selection? Are there too many exclusions that are not well justified, or are important exclusions overlooked? Are there postenrollment exclusions that could potentially bias the sample? Is availability of adequate numbers of participants from the sampling frame assured? Are there enough participants in the setting to do this study as described? Checklist for the Grant-Writing Process (III) Section and Topic Questions To Address Data collection/procedures Are procedures well-described? Are there quality assurance measures for data collectors? Is there adequate description of study instruments/measures? Are standardized, validated measures used? Are there concerns about validity or reliability of data collection methods? Are all important study variables described and collected? Are there extraneous variables that are never used in subsequent analyses? Checklist for the Grant-Writing Process (IV) Section and Topic Questions To Address Outcome Is the outcome adequately described, defined, and specified? Are the validity, reliability, and performance characteristics of the outcome measure provided? Are the outcome data collected by researchers who are blinded to the study hypotheses and study group assignment? Checklist for the Grant-Writing Process (V) Section and Topic Questions To Address Intervention (if applicable) Does the intervention appear potent (that is, is it likely to be effective as described) Is the intervention well-described—can you understand what was done, or is it a “black box”? Is the protocol standardized so that it is likely to be reproducible in other settings? Is the intervention administered by a separate individual/group not involved in outcome assessment? Is there blinded administration of the intervention protocol (e.g., double-blinding of drug trial)? Is there randomization to study groups? Is there likely to be potential bias in the way the patients were allocated to treatment groups or received the intervention? Will adherence to the intervention be monitored? Will the effects of nonadherence be considered? Are safety issues regarding the intervention addressed? Is an appropriate control group selected? Are issues of contamination or co-interventions in the control group addressed? Checklist for the Grant-Writing Process (VI) Section and Topic Questions To Address Data analysis Have you consulted a biostatistician? Are the analytic approach and structure of analyses adequately described? Will an intention-to-treat approach be used? Is there adequate attention to potential confounders? Are there sample size or power calculations? Are attrition rates/losses provided? Do they appear realistic/justified? Do anticipated losses threaten the validity of the study? How will missing data and nonresponses be handled in analyses? Checklist for the Grant-Writing Process (VII) Section and Topic Summary Questions To Address Are the strengths and weaknesses of the grant presented? How do the weaknesses affect the validity or interpretation of the study results? Are potentially fatal flaws unaddressed? Are the implications of the work discussed? 執行構想與擁抱失敗 • 執行靠的是堅持與應變,要的是勇氣,不是資源 • 失敗,是正常的 • 別怕跌倒,才有大躍進 Challenges vs. Chances • The pessimist sees difficulty in every opportunity • The optimist sees the opportunities in every difficulty Keywords for Funding • Innovation • Hypothesis-driver • Mechanistic • Use of state-of-the-art methodology • Feasibility • Biomedical importance • 練成功/成大功 • No magic, only basic • 堅持/ 不忘本 5W2H Why 為什麼必須做此計畫? When 時間表如何? Background Significance Time line What 要做什麼? Where 要在那裡執行? Hypothesis Specific aims Environment Institutional Support How 以什麼樣的方法執行? Methods Who 由誰來做 Track Record Preliminary results How much 預算多少? Expense 孟子離婁篇:徒善不足以為政, 徒法不足以自行 成功鐵三角 Individual (Perseverance) Environment (Supportive) Mentor or Senior Investigator (Experience & Advice) Calvin Coolidge (1872-1933) “Press on: nothing in the world can take place of perseverance Talent will not; nothing is more common than unsuccessful men with talent Genius will not; unrewarded genius is almost a proverb Education will not; the world is full of educated derelicts Persistence and determination alone are omnipotent” How to Get a Grant Funded-Take Home Message • Writing grant applications is a skill that researchers must acquire • Decide which grant making body to approach at the onset; make sure that proposed research is relevant to the funding body • Write focused, succinct, clear applications that follow the guidelines set down • Learn from rejections 謝謝聆聽 National Taiwan University Hospital