IDF-BRiDGES Translational Research Grants Course

1. IDF-BRiDGES Translational Research Grants Course BRIDGES, an IDF project supported by an educational grant from Eli Lilly and Company Course and Materials developed by K.M. Venkat Narayan and Mary Beth Weber Rollins School of Public Health, Emory University

2. Acknowledgements • Thoughts, comments, slides, and help from the following are acknowledged: • Frank Vinicor • Edward Gregg • Carol Mangione • Monique Hennink • Russell Glassgow • Michael Engelgau • David Williamson • Ping Zhang • Mark Hutcheson

3. Introduction to Translational Research

4. DISTRIBUTION AVAILABILITY EFFICIENCY EFFECTIVENESS EFFICACY FUNDAMENTAL RESEARCH DETSKY, 1990

5. Translational research transforms currently available knowledge into useful measures for everyday clinical and public health practice. Translational research aims to assess implementation of standards of care, understand the barriers to their implementation, and intervene throughout all levels of health care delivery and public health to improve quality of care and health outcomes, including quality of life. Narayan et al. Ann Intern Med, 2004

6. Knowledge Need

7. Knowledge Need

8. Changing practice Effectiveness Patient, provider and system factors Generalizability Focus on common Benefit as absolute Quality as relative and dynamic Optimal health for many Etiological vs. translational research • Understanding cause • Efficacy • Patient factors (largely biological) • Internal validity • Focus on rare • Benefit as relative • Quality as absolute and static • Perfect health for few Narayan et al. Diabetes Care

9. Types of translational research • Phase one translation, usually dubbed “bench to-bedside,” applies basic scientific discoveries to human health care under controlled conditions, i.e., clinical research. • Phase two translation promotes the adoption of the fruits of promising clinical research by the community-based health care system under uncontrolled and (often) uncontrollable conditions. http://www.niddk.nih.gov/fund/other/Diabetes-Translation/conf-publication.pdf

10. What a reasonable observer assumes: • That promising new biomedical and behavioral science would be quickly and universally offered to any patient who might benefit from it • That the power of the new science to improve the human condition should be sufficient to propel widespread adoption of the new science by our health care system and the patients it serves

11. Unfortunately, this is rarely the case • In the real world, phase two translation stumbles unguided towards a very uneven, extraordinarily incomplete, and socially disappointing state of affairs

12. However, that can change • Implementation of well-designed translational research projects • This seminar will provide you with information on: • Necessary project components • Tips for grant writing • Avoiding common pitfalls

13. Grant Writing for Translational Research

14. Presentation overview • Study aims and objectives • Background • Research plan • Sustainability • Budget

15. 1. Study Aims and Objectives

16. Aims and objectives Aim: To evaluate the effectiveness, cost-effectiveness, and sustainability of a community-based diabetes prevention program in Chennai, India using a randomized controlled trial, with 700 people with pre-diabetes randomized to either standard lifestyle advice or a culturally specific, low-cost, intensive lifestyle intervention • Objective 1: To evaluate effectiveness of the lifestyle intervention by assessing between group changes in the following: • Primary Outcome: incidence of T2DM • Secondary Outcomes: body weight, percent body fat, body mass index, waist-to-hip ratio, fasting glucose, blood pressure, plasma lipids, activity, and diet

17. Aim: To evaluate the effectiveness, cost-effectiveness, and sustainability of a community-based diabetes prevention program in Chennai, India using a randomized controlled trial, with 700 people with pre-diabetes randomized to either standard lifestyle advice or a culturally specific, low-cost, intensive lifestyle intervention • Objective 1: To evaluate effectiveness of the lifestyle intervention by assessing between group changes in the following: • Primary Outcome: incidence of T2DM • Secondary Outcomes: body weight, percent body fat, body mass index, waist-to-hip ratio, fasting glucose, blood pressure, plasma lipids, activity, and diet Aim: Clearly states the point of the study, including important details about the research. The aim can also be stated as a question or as a hypothesis.

18. Aim: To evaluate theeffectiveness, cost-effectiveness, and sustainabilityof a community-based diabetes prevention program in Chennai, India using a randomized controlled trial, with 700 people with pre-diabetes randomized to either standard lifestyle advice or a culturally specific, low-cost, intensive lifestyle intervention • Objective 1: To evaluate effectiveness of the lifestyle intervention by assessing between group changes in the following: • Primary Outcome: incidence of T2DM • Secondary Outcomes: body weight, percent body fat, body mass index, waist-to-hip ratio, fasting glucose, blood pressure, plasma lipids, activity, and diet

19. Aim: To evaluate the effectiveness, cost-effectiveness, and sustainability of a community-based diabetes prevention program in Chennai, India using arandomized controlled trial, with 700 people with pre-diabetes randomized to either standard lifestyle advice or a culturally specific, low-cost, intensive lifestyle intervention • Objective 1: To evaluate effectiveness of the lifestyle intervention by assessing between group changes in the following: • Primary Outcome: incidence of T2DM • Secondary Outcomes: body weight, percent body fat, body mass index, waist-to-hip ratio, fasting glucose, blood pressure, plasma lipids, activity, and diet

20. Aim: To evaluate the effectiveness, cost-effectiveness, and sustainability of a community-based diabetes prevention program in Chennai, India using arandomized controlled trial, with 700 people with pre-diabetes randomized to either standard lifestyle advice or a culturally specific, low-cost, intensive lifestyle intervention • Objective 1: To evaluate effectiveness of the lifestyle intervention by assessing between group changes in the following: • Primary Outcome: incidence of T2DM • Secondary Outcomes: body weight, percent body fat, body mass index, waist-to-hip ratio, fasting glucose, blood pressure, plasma lipids, activity, and diet

21. Aim: To evaluate the effectiveness, cost-effectiveness, and sustainability of a community-based diabetes prevention program in Chennai, India using a randomized controlled trial, with 700 people with pre-diabetes randomized to either standard lifestyle advice or a culturally specific, low-cost, intensive lifestyle intervention • Objective 1: To evaluate effectiveness of the lifestyle intervention by assessing between group changes in the following: • Primary Outcome: incidence of T2DM • Secondary Outcomes: body weight, percent body fat, body mass index, waist-to-hip ratio, fasting glucose, blood pressure, plasma lipids, activity, and diet

22. Aim: To evaluate the effectiveness, cost-effectiveness, and sustainability of a community-based diabetes prevention program in Chennai, India using a randomized controlled trial, with 700 people with pre-diabetes randomized to either standard lifestyle advice or a culturally specific, low-cost, intensive lifestyle intervention • Objective 1: To evaluate effectiveness of the lifestyle intervention by assessing between group changes in the following: • Primary Outcome: incidence of T2DM • Secondary Outcomes: body weight, percent body fat, body mass index, waist-to-hip ratio, fasting glucose, blood pressure, plasma lipids, activity, and diet Objective: Describes how the investigators will answer the research question

23. Aims and objectives • Aim 1: Can peer education and support groups be used to influence lifestyle choices and prevent obesity in men living in Karachi?

24. Aim example • Aim 1: Can peer education and support groups be used to influence lifestyle choices and prevent obesity in men living in Karachi? • Problems: • Study design? • Lifestyle choice outcome is vague

25. Aims and objectives: General information • Begin by summarizing the need for this research • Clearly state your main research objective in the form of aims or a hypothesis • Briefly describe how you are going to do the project in objectives or a paragraph • Length: 1-2 pages

26. Aims and objectives: General information • After reading your aims section, the reader should be able to: • State the need for your project • Agree that the project is needed • Summarize the main purpose and broad methods of your project • Be excited and interested to read the rest of your proposal

27. Questions and discussion

28. 2. Background

29. Background • Summarize pertinent literature • The problem your project is addressing • Other studies addressing this problem • Highlight what is missing in the literature • The research that you are translating • Support for the theories and methods that you are using • End with a clear summary • Preliminary research • Length: 1-2 pages

30. Background • Your background sections should be: • Thorough but succinct • Well-written • Easy to read and follow • Subheadings • Pertinent

31. Questions and discussion

32. 3. Research Plan

33. Study design Outcomes Study testing Study Sample Timeline Intervention Data analysis plan Key personnel Ethical Issues Research plan components

34. Study design Outcomes Study testing Study Sample Timeline Intervention Data analysis plan Key personnel Ethical Issues Research plan components

35. How to select the best study design • Study design • Should be closely linked to the purpose of the evaluation • Should build on a theoretical framework of behavioral change • Should consider randomized designs first • Non-randomized designs or designs where the unit of randomization is other than the participant may be the most appropriate for translational research questions

36. Study design selection • Challenge in translational research is that the interventions are usually complex (multifaceted with simultaneous changes in different parts of the organization) • Researcher has variable control over how the intervention is implemented Eccles M, et al. Qual Saf Health Care 2003;12;47-52

37. Critical steps in the research plan before the definitive study • Development of a theoretical basis for the intervention • Define the components of the intervention • Exploratory studies of observational data + qualitative research to further refine the intervention and planned evaluation • Definitive evaluation Eccles M, et al. Qual Saf Health Care 2003;12;47-52

38. Types of studies Quantitative non-experimental designs Quantitative experimental designs Randomization Qualitative Multi-level, multi-factorial interventions Community-based participatory research

39. Quantitative non-experimental designs • Cross-sectional designs • Uncontrolled before and after (longitudinal observational cohort studies) • Controlled before and after • Time series analyses • In translational research there can be political, practical, and ethical barriers to randomized designs – but randomized designs should first be considered

40. Quantitative non-experimental designs • May have little control over the implementation of the intervention… • Strength: very “real world” • Weakness: hard to know what really happened or which “outcomes” are likely to have changed • Researcher should document implementation across heterogeneous settings • Lack of randomized controls is always a threat to internal validity but this trade-off must be placed in context of research question and study goals

41. Uncontrolled before and after • Simple to conduct • Secular trends make it difficult to attribute changes to the intervention • Probably over-estimate the benefit from quality improvement interventions

42. Controlled before and after • A control population with similar characteristics is identified • Baseline and post-intervention data are collected on both the control and intervention populations • Protects against secular trends • Even in well-matched groups, baseline characteristic can differ

43. Controlled before and after • Looking at the significance of within group change is not appropriate • Analyses of these data need to account for clustering by site especially if the intervention is delivered at the organizational level

44. Time series designs • Does the intervention improve care more than the observed secular trend? • Requires the collection of data multiple times both before and after so that you understand the magnitude of the secular trend • Analysis must account for the auto-correlation of data collected at multiple time points • Strength is that you do not need a control group • Weaknesses are that you need to collect data multiple times and the design does not protect against other events occurring at the same time as the intervention

45. Types of intervention studies • Randomized or quasi-randomized trials • Interrupted time series (ITS) • Defined intervention • 3 points in time before and after • Non-randomized studies with controls at a second site • Data collected before and after the intervention • Key to interpretation hinges on comparability of the sites • Most are evaluations within systems rather than between systems

46. Quantitative experimental designs • Individual patient-level randomized controlled trials • Cluster randomized controlled trials • Strongest designs to establish a causal relationship • Often times difficult to implement…but considering them is important

47. Randomized controlled trials • Considered to be the gold standard • Randomly allocated to either intervention or control group • Best way to insure that both known and unknown factors that may influence effectiveness of the intervention are balanced in the two comparison groups • Time consuming, expensive, complex, may require a large number of clusters, tight inclusion criteria limit generalizabilty • May not tell you whether an intervention will improve routine practice

48. Randomization vs. random sample • Randomization = process of randomly allocating people to different study groups • Control for confounding • Random sample = process of selecting a random group from a larger study population • Generalizability

49. Level of randomization • Patient • Health care professional • Practice/hospital • Provider group • Health plan • Community LOW LEVEL CONTAMINATION HIGH LEVEL POWER, LOGISTICS

50. Level of randomization • At higher levels of randomization measure-ment of pre-intervention characteristics is critically important • Consider stratification on baseline characteristics that are likely to influence the effectiveness of the intervention • Cluster randomization is likely to violate the assumption of independence of observations within a cluster • Two patients in same practice are likely to be more similar than three from different practices • Need to be able to estimate the intracluster correlation coefficient (ICC)