To grant you an edge: Part 2. Tactical tips for addressing specific aspects of biomedical research proposals
2022; American Physiological Society; Volume: 132; Issue: 6 Linguagem: Inglês
10.1152/japplphysiol.00078.2022
ISSN8750-7587
Autores Tópico(s)Health and Medical Research Impacts
ResumoViewpointTo grant you an edge: Part 2. Tactical tips for addressing specific aspects of biomedical research proposalsDouglas R. SealsDouglas R. SealsDepartment of Integrative Physiology, University of Colorado Boulder, Boulder, ColoradoPublished Online:13 Jun 2022https://doi.org/10.1152/japplphysiol.00078.2022This is the final version - click for previous versionMoreSectionsPDF (948 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat In Part 2 of this Viewpoint on competitive grant-writing practices (1), I share selective thoughts and recommendations for developing specific aspects of biomedical research proposals. In the first section, I present a brief discussion of the common dilemma of whether to pursue a "pilot" versus a "regular" research project grant funding mechanism to provide support for a new study. In the second section, I share some suggestions for developing certain key components of an application, including the specific aims, assembling the investigative team, choosing/presenting preliminary results, and recommendations for establishing proper scientific rigor and reproducibility. In the third section, I present several considerations for effectively developing and successfully defending grant budgets.As in the other parts of this Viewpoint (2–3) and previous commentaries in this series (4–6), I acknowledge up front that the impressions and tips shared here are based largely on my personal instincts, observations, and biases. I also wish to reinforce that the primary target audience for this discussion is early career stage investigators with limited grant writing experience, although I welcome established investigators to read and compare notes.TARGETING A PILOT VERSUS REGULAR RESEARCH PROJECT GRANT MECHANISMOne of the frequently asked questions (FAQs) I receive, especially from early-stage investigators, is whether they should choose a pilot or a regular research project grant application mechanism to provide funding for a new research study. My answer is always that the choice depends on the situation.ScopeOne major factor in making an informed decision is the scope of the idea and putative research plan. If the work will address one or two primary aims and can be completed within a 1- or 2-yr timeline, then a pilot project grant mechanism may be worth further consideration. Beyond that scope, however, a regular research project grant application mechanism with higher annual budget capacity over a 3- to 5-yr award period likely will be necessary to accommodate both a greater breadth of scientific objectives and the funding required to support the more extensive work proposed (Fig. 1).Figure 1.Choosing between a pilot vs. regular research project grant application mechanism. Choosing between a pilot (upper arrow and above) and regular research project (lower arrow and above) grant mechanism depends on the setting, including 1) the scope and duration (year blocks) of the research aims/plan; 2) the quantity of preliminary results (materials above year blocks) supporting the proposed study aims and hypotheses; and 3) whether a particular grant mechanism involves a pay line (funding cut-off) benefit for the applicant. Illustration by Steve Graepel.Download figureDownload PowerPointPreliminary ResultsAnother key factor is the available preliminary results supporting the feasibility of the aims and working hypotheses. Modest preliminary data directly supporting only one or two uncomplicated aims (versus several aims and sub-aims) and/or based on a small sample size may only be adequate to justify an additional pilot investigation. In contrast, preliminary results supporting the feasibility of multiple aims and sub-aims or obtained on a larger sample size provide a much stronger foundation for pursuing a regular research project grant mechanism (Fig. 1).Career Status of PIStill another consideration is the career status of the PI (principal investigator) and the available funding mechanisms for early-stage investigators created by the grant agency. For example, in the National Institutes of Health (NIH) system, the "pay line" (merit score) for funding a standard research project ("R01") grant application mechanism is set lower (more lenient) for early-stage investigators (i.e., investigators within 10 yr of obtaining their terminal academic degree who have yet to receive a major research project award) compared with established PIs (who previously have obtained such awards). However, the NIH pilot grant mechanisms ("R03, R21") do not have special pay lines for early-stage investigators; the latter compete with all PIs for those limited funds. As such, if the grant writer has early-stage investigator status and their envisioned research aims meet even the lower standard of scope expected for a standard research project funding, I often recommend they pursue that mechanism over a pilot study application (Fig. 1). Moreover, even though early-stage investigators with new laboratories may have fewer preliminary data to present than more senior PIs, that factor is usually taken into consideration by grant reviewers, further arguing for the junior applicant pursuing the nonpilot proposal approach if other considerations can be met.TACTICAL TIPS FOR ADDRESSING KEY ASPECTS OF GRANT APPLICATIONSSpecifically Start with the Specific AimsIn my opinion, the single most important component of the grant-writing process is developing a scientifically compelling specific aims page because it establishes the initial, foundational vision of the proposed research. Creating a sound early draft of that document, including 1) a distinct research theme to establish the conceptual framework of the project; 2) a summary of published and preliminary research that, together, establish a strong scientific premise for the proposed project; and 3) clearly described working hypotheses and corresponding specific aims, is the crucial first step in constructing a competitive grant application. The description of the hypotheses and aims dictates not only the preliminary results needed to support the feasibility of the proposed research but also the study design, experimental methods, investigator expertise, and resources (facilities, major equipment, staff, supplies, budget, etc.) that will be required to provide the results necessary to definitively test the working hypotheses. In other words, the specific aims page represents an essential roadmap for planning all other sections of the grant application (Fig. 2).Figure 2.Specifically start with the specific aims. The first step in constructing a competitive research project type grant application is to create a scientifically compelling specific aims page because it provides an essential "roadmap" for developing all other supporting elements of the proposal, including the 1) investigator expertise (key personnel) required; 2) experimental methods; and 3) major research equipment and facilities needed. Illustration by Steve Graepel.Download figureDownload PowerPointThat said, the specific aims page should be considered a "living document" during the grant writing process rather than a static script. As the proposal develops, you likely will need to return to this page several times to modify certain information to maintain internal consistency with other sections of the application (see Part 1 of this Viewpoint). For example, when developing the background and significance section of the proposal you may identify some inconsistency in the presentation of the content supporting the scientific premise on the specific aims page, perhaps due to the discovery of a new original research paper that changes your view of the published literature pertaining to your topic. Another possibility is that the preliminary results obtained on a key pilot experiment turn out to be contrary to one of your working hypotheses, or perhaps an updated power calculation conducted by your biostatistician suggests that the original description of one of your aims is no longer feasible.The key message here is that although it is important to establish a well-conceived initial draft of your specific aims page from which to develop the other parts of the proposal, from that point on you should work interactively between the aims page and other parts of the application as you encounter problems or limitations in one section that, upon correcting, create inconsistencies in other sections. Move seamlessly and repeatedly back and forth among the component parts of the proposal—including the specific aims page—as the grant-writing process proceeds until the specific aims page and other contents throughout the application are precise, in sync, and error-free.Keys To Developing Key PersonnelAs noted previously, the qualifications of the PI and investigative team are one of the major review criteria for research project type grant applications. In NIH terminology, this group is described as the "key personnel," defined as all individuals who contribute to the scientific development or execution of a research project in a substantive, measurable way.Identifying required expertise.The initial step in establishing the key personnel for a grant application is identifying all areas of expertise required to successfully conduct the proposed research (literally, make a list). Armed with that information, determine which, if any, of those areas you as PI might be perceived by reviewers as lacking sufficient expertise (i.e., conceptual knowledge, technical skills, documented experience, and publication/funding success) to conduct the work. All such areas must be supported by experts either within or outside your existing laboratory workforce. The process almost always necessitates recruiting one or more external co-investigators from elsewhere within or outside your institution to fill gaps in your laboratory's expertise. This is the conventional approach and what peer reviewers expect to see in a competitive grant application. Indeed, a significant part of the score you will receive for the qualifications-of-the-investigators component of the review criteria will be based on how well all the relevant areas of the proposed science are covered by the key personnel you have assembled (Fig. 3).Figure 3.Keys to developing key personnel. To develop the "superhero" team of co-investigators, consultants, and/or staff required to successfully conduct the proposed research, you as the principal investigator must 1) identify all areas of investigative expertise required and recruit an appropriate candidate for each role; 2) clearly and distinctly define each role to establish the availability of the necessary expertise while avoiding any perceived overlap; 3) provide appropriate budgetary support for each role; and 4) generate effective biosketches describing the relevant expertise of each member of the team. Illustration by Steve Graepel.Download figureDownload PowerPointDescribing distinctive roles.Once the key personnel are in place, the major challenge is properly describing their individual roles in the research project. You must define each role in a manner that is distinctive and complementary in that the responsibilities described do not overlap conceptually or functionally with the duties of other personnel. Failing to do so adequately is one of the most common mistakes made by grant writers when presenting the required information on the investigative team. Clearly depicting the discrete roles of your key personnel also is an important "exercise" for you as the PI to confirm that you are constructing the most effective, yet organizationally efficient, investigative team possible to successfully conduct your research project.Requesting appropriate budget support.In most cases, reviewers also will expect that your proposed key personnel will be supported from the budget of your grant application. A co-investigator who is described as having a significant role in the project without compensation (e.g., because you were unable to fit the cost into the limits of your budget) likely will be viewed by reviewers with skepticism as to whether the co-investigator will, in the end, perform the duties described. Similarly, reviewers also will expect the proposed amount of time ("effort") that each member of the investigative team will dedicate to align with the description of their respective duties. An individual with responsibilities that appear to require at least 50% of their workweek but whose effort on the application is described as "10%" of their appointment will draw suspicions from reviewers, as will the opposite situation in which the requested personnel effort appears far too great for the modest involvement described.The importance of the grant-formatted curriculum vitae.An essential tool for describing (and defending) key personnel, particularly the co-investigators, is the curriculum vitae (CV or "biosketch" in NIH terminology) section of the grant application. The individual CV/biosketch should reinforce the qualifications (technical skills, knowledge, and experience) of each member of the key personnel for the respective role and specific set of duties assigned to them. For co-investigators, the appropriateness of the individual for the proposed responsibilities is established in part by their history of professional appointments, record of publications and research funding, and overall research experience. Importantly, the CV/biosketch should be "personalized" (customized) for the grant application in question, including a description of their responsibilities in the project, how they are qualified to perform those duties and any history of prior successful collaboration between that person and the PI (you) and other co-investigators. Moreover, the person's experience and publications most closely related to their proposed role and the theme of the research project should be emphasized rather than highlighting expertise unrelated to their duties or the focus of the project (i.e., cut and pasted from another recent grant application).To reduce the burden placed on a co-investigator for creating this customized information (they probably will not be familiar with the details so this can be a significant time investment for them), while providing you a measure of quality control to create the most effective end product, you might offer the option of forwarding a recent version of their CV/biosketch that you and your grant-writing team can modify (personalize) on their behalf. Most co-investigators will be more than happy to accept your offer! Regardless of how you achieve it, the overarching goal of the information presented in the CV/biosketches of key personnel should be to allow a busy, time-strapped reviewer to determine with minimal effort if the credentials of each member of the investigative team are appropriate for the research responsibilities described.Preliminary Thoughts on Preliminary ResultsPresenting preliminary results in a biomedical grant application is tricky. Peer reviewers expect you to present preliminary data to show both the feasibility of the specific aims (e.g., your ability to successfully conduct the proposed experimental procedures) and direct experimental support for the working hypotheses. Here are some selective thoughts and recommendations regarding generating, choosing, and presenting preliminary results in biomedical research grant applications.How much is enough?A major challenge in presenting preliminary results involves the "Goldilocks" principle: you should not present too little or too much, but rather just the "right" type and amount to establish the feasibility of your proposed aims and hypotheses (Fig. 4). In some cases, the issue may be moot because you have limited preliminary data to work with and you will need to present most if not all of it. If you do have significant, perhaps even substantial, preliminary results at your disposal, you will need to decide what to present and how to present it.Figure 4.Preliminary results: how much is enough? The quantity of preliminary results to present in your grant application is governed in part by the "Goldilocks principle." Too much creates a burden for reviewers to evaluate and may distract them from focusing on the most important data. Too little may cause reviewers to question the foundation of preliminary evidence supporting the scientific premise and feasibility of the proposed aims and hypotheses. "Just the right amount" to facilitate reviewer evaluation, while emphasizing the key data supporting feasibility should be the goal. Illustration by Steve Graepel.Download figureDownload PowerPointType of grant mechanism. One factor to consider is the type of grant mechanism you are developing. A conventional, multiyear grant mechanism for research project support will require more preliminary results to meet reviewer expectations than a 1- or 2-yr grant application to fund a pilot study. That makes sense. However, what early-career stage investigators may not fully comprehend is that preliminary data probably should be presented even when the instructions clearly state that no preliminary results are required, as is the case with some grant mechanisms designed to support pilot investigations or, perhaps, research fellowship proposals. Such situations can arise because, again, grant agency officials write the instructions for developing grant applications, but peer investigators review those applications. Reviewers likely will expect to see preliminary results supporting at least some of the aims and hypotheses because that is the established cultural norm for research proposals in general. As emphasized in Part 1 of the Viewpoint (2), this is another example of why it is essential to understand the peer review process and peer reviewers and to write grant applications for reviewers, not program officers (or for the instructions they create). In this case, grant reviewers may interpret (or ignore) the proposal instructions in a manner that could inadvertently weaken the competitiveness of your application if you are unaware of the conditions in the "real world."Preliminary results for some or all the research aims? Another FAQ is whether grant reviewers will expect you to present preliminary data supporting all your proposed aims and hypotheses or only some aims. Again, the answer depends on the type of grant application, as well as the applicant. For conventional research project grant applications submitted by established PIs, you likely will need to provide preliminary results supporting most if not all your main aims. If the final aim is framed as "exploratory," reviewers may (or may not) lower their expectations. Alternatively, if a research project type grant application is submitted by an early-stage investigator, fair-minded reviewers should expect (and require) fewer preliminary data, e.g., perhaps only for two of the three proposed aims/hypotheses and perhaps fewer preliminary results overall. Same situation for research career development proposals: you may reasonably assume lower overall requirements for preliminary data compared with a standard research project proposal submitted by an experienced PI.Data on how many subjects? A related question concerns the amount of preliminary data needed to support a particular aim or working hypothesis. For established PIs submitting conventional research project grant applications, I have always operated with the strategy that it is more advantageous to have some supporting preliminary results on most or all your main aims/hypotheses versus more extensive supporting data on only one or two. That approach has been successful for us through the years, so there is quite a bit of empirical evidence for that approach. However, it is important to understand that some reviewers expect a sample size sufficient to show statistically significant differences in your main comparisons when presenting preliminary data. When the preliminary results in question pertain directly to one of your proposed aims this expectation likely will strike you as confusing, paradoxical, and/or unfair because, well, it is! Why do I need to show statistically significant differences if that is the exact question I am addressing in Aim 1? Indeed, if you show significant differences in your preliminary results, would you not be risking criticism by another reviewer that you have already answered the question and achieved the aim? Welcome to the complicated, irrational, and often frustrating life of a grant applicant interfacing with an individually minded group of peer reviewers!One strategy to consider when attempting to navigate the precarious space between these potential criticisms is to gather sufficient data to show statistical significance but, having presented those as preliminary results, argue for the importance of the proposed research on the basis that the observations need to be confirmed in a larger group (or groups) of biological samples, cells, animals, or people. Conversely, in situations in which you are unable to obtain results on enough subjects to test for statistical significance, you might explain that you were unable to perform inferential statistics (to test for statistical significance) because the low group numbers did not allow sufficient statistical power to meet the assumptions of the analyses and, therefore, the group or condition comparisons in question are presented using only descriptive statistics. Neither of these strategies will guarantee a successful outcome in every case. However, such arguments should resonate with many, if not most, experienced, objective reviewers, which is all you can hope for in that setting.How to present?A few suggestions for enhancing the readability of preliminary results in your biomedical research proposal.Present your preliminary results in the clearest, most straightforward, well-organized manner possible. Most preliminary data are presented in figure format, usually in multipanel figures, although short tables also can be used effectively. Whether using a multipanel figure or a table, be aware that presenting every potential piece of preliminary data can lead to reviewer overload. Too many figure panels or cells of a table can make reviewers glassy-eyed, risking the possibility of them giving up on that segment of the preliminary results and "moving on"—perhaps with a less favorable attitude toward evaluating the entire remainder of the proposal (you never know what might trigger a change in attitude). Not to mention the practical fact that you will be limited by mandatory page restrictions. As such, if you are in the fortunate situation of having extensive preliminary results to work with, you will need to prioritize what to present. In those instances, I recommend that you identify the preliminary results that most directly and rigorously support each aim or working hypothesis (Fig. 4). After those data are emphasized, if sufficient space remains, you can consider presenting additional preliminary results at the next level of priority and so on, thoughtfully monitoring the extra cognitive burden being placed on reviewers as you add information.The most efficient use of space is to describe the preliminary results in the narrative text while referring to the relevant figure numbers and panel letters of interest (vs. describing the information in the text and summarizing the results in a separate legend below the figure). When describing key findings in the text of the preliminary results section, choose your wording while simultaneously viewing the data being presented in the corresponding figures or tables from the reviewers' perspective. This approach will help ensure proper conceptual alignment between the written text and supporting illustrations.Do not under any circumstances reduce the size of the figures or tables to the point that the resolution of important detail may be lost, making it difficult for reviewers to capture and interpret the essential information with reasonable effort. This is one of the most common grant-writer mistakes; too many panels or panels that are too small or otherwise difficult to decipher, or both, can be a highly frustrating experience for reviewers, and they will note that (negative) experience in their critiques. If you must create additional space for an appropriately sized figure, consider deleting or shortening text, especially descriptions of methods that can be alternatively obtained from the laboratory's published original research articles.Use color contrasts to your advantage when attempting to depict different components of an integrative schematic figure or when presenting data from different groups or conditions using bar or line graph formats. Again, this lessens the time and effort required by reviewers to identify and interpret the information being presented.Effective presentation of preliminary results that support the key specific aims and working hypotheses of a biomedical grant application is a challenging task. Developing a successful, reviewer-friendly approach, including some or all the recommendations above, will pay important dividends for you and your research program.Be Reproducibly Rigorous about Rigor and ReproducibilityCritical evaluation of the "rigor and reproducibility" of the proposed research is now a major point of emphasis by peer reviewers of biomedical grant applications. This emphasis stems in large part from recent recognition and acknowledgment of poor reproducibility of findings from preclinical studies but is just as relevant for clinical research performed on human subjects.Requirements for rigor and reproducibility in grant applications.In the United States, the NIH requires grant applicants to describe their plans for addressing four key areas of this topic (https://grants.nih.gov/policy/reproducibility/guidance.htm):The rigor of prior research, established by describing the general strengths and weaknesses in the rigor of both published and unpublished work that, taken together, establishes the need (experimental basis) for the new research you are proposing, as well as how your investigative plan will address existing weaknesses in the field.The scientific rigor of your proposed research is defined as "the strict application of the scientific methods to ensure robust and unbiased experimental design, methodology, analysis, interpretation, and (transparent) reporting of results."Consideration of relevant biological variables, including sex and age, in the proposed research design, analyses, and reporting of results.Authentication of key biological and/or chemical resources proposed for use (e.g., cell lines, reagents, antibodies, etc.).How to address rigor and reproducibility.Because peer reviewers are laser-focused on these issues, you will need to thoughtfully address all facets of rigor and reproducibility in your grant proposal. Doing so includes the following efforts (Fig. 5):emphasizing the strengths and weaknesses of prior research, including both the published literature and your preliminary results;clearly stating the research hypotheses and associated specific aims of the proposed research;describing the rigor of your experimental design, including randomization of subjects to treatment groups and appropriate blinding of the investigators to those group assignments to reduce bias;proposing the use of "gold standard" measurement techniques whenever possible, including procedures that strictly follow international scientific standards with established reproducibility;proposing studies that are adequately powered for primary outcome variable(s) and properly supported by a detailed statistical analysis plan;inclusion of both males and females with a comprehensive statistical analysis plan that considers factors such as sex, age, and health conditions as potential covariates; andyour record of consistent, transparent reporting of results and publication of findings (whether "positive" or "negative") in peer-reviewed scientific journals.Figure 5.Establish rigor and reproducibility. Establishing a strong, multicomponent foundation of rigor and reproducibility is essential when developing a competitive biomedical grant application. Illustration by Steve Graepel.Download figureDownload PowerPointThe latter point is important for all types of research, including reporting findings from clinical trials in humans. In the past, numerous randomized clinical trials that observed negative results (e.g., showing no significant therapeutic benefits) from an experimental treatment failed to report those findings. This situation created multiple instances of evidence bias on specific topics of medical relevance in the peer-reviewed scientific literature. Consequently, grant funding agencies like NIH are reemphasizing the importance of reporting the results of all clinical trials to reduce the occurrence of "positive results" bias.Additional tips.Ultimately, there are multiple approaches for boosting rigor and reproducibility to increase the competitiveness of your grant proposal. In closing this part of the discussion, here are three additional suggestions for enhancing research rigor that reviewers will expect to see and/or are explicitly requested in proposal instructions (Fig. 5).Include an "airtight" interpretation-of-results section. A critical aspect of promoting rigor in your study design and experimental approach is providing reviewers with a detailed description of how all possible results will be interpreted to either support or refute your working hypotheses. Again, not including this information, particularly in complex research projects that involve multiple groups, conditions, treatments, and/or outcome measures, is a common mistake made by both inexperienced and more seasoned grant writers. Our ap
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