Proposal Writing 2: Preparing an Application for Career Development or New Investigator Awards

Shehnaz K. HussainAssistant ProfessorDepartment of Epidemiology, UCLAskhussain@ucla.edu

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Outline and Objectives

Part I: Intro to Career Development Awards (CDAs) and New Investigator Awards

What are they? Who applies for them? Which agencies have them? What are the most important components of the application?

Part II: Focused Discussion of the Research Plan

study design, statistical analysis and power, problems and pitfalls

Part II: Practical demonstration of sample size and power calculation

E, G, E*G

Part I: Description of CDAs and New Investigator Awards

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Career Development Awards: What are they?

Awards for individuals with doctoral degrees who demonstrate need for additional training

Up to 5 years of support for salary (up to $100,000/yr)

research ($30-75,000/yr)

Multiple interconnected elements

Intent is to prepare investigator for R01-type grant submission

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Career Development Awards: NIH K series (1)

Types of awards:K01: Mentored Research Scientist DevelopmentKO7: Mentored Research Career DevelopmentK08: Mentored Clinical Scientist DevelopmentK12: Mentored Clinical Scientist DevelopmentK23: Mentored Patient-Oriented Research Dev. K25: Mentored Quantitative Research DevelopmentK99/R00: NIH Pathway to Independence Award

http://grants.nih.gov/training/careerdevelopmentawards.htm

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Career Development Awards: NIH K series (2)

Which K award is right for you?Terminal doctoral degreeYears of mentored support requiredSpecific research area

http://grants.nih.gov/training/kwizard/index.htmhttp://grants.nih.gov/grants/guide/search_guide.htm

What types of awards does NCI fund?

http://crisp.cit.nih.gov/http://fundedresearch.cancer.gov/search/SearchForm

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Career Development Awards: NIH K series (3)

Pre-doc Post-doc Jr. Faculty Independent

Mentored

T32

T90/R00

R25

F31

T32

T90/R00

R25

K12

F32

K07

K22

R25

K08

K01

K07 K08

R01

K22

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0

500

1,000

1,500

2,000

2,500

3,000

3,500

4,000

4,500

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007Fiscal Year

Num

ber o

f Aw

ards

Data provided by the Division of Information Services, Reporting Branch

Trends in Number of Funded Research Career Awards

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0

500

1,000

1,500

2,000

2,500

3,000

3,500

4,000

4,500

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

KL1KL2K99K17K15K20K26K11K06K25K04K16K14K18K22K30K12K05K07K24K02K23K01K08

Fiscal Year

Num

ber o

f A

war

dsTrends in Number of Funded Research Career Awards By Type

Data provided by the Division of Information Services, Reporting Branch

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Participating NIH Institutes and Centers

K07 Applications and Awards by Participating Institutes: FY 2007N

umbe

r of A

pplic

atio

ns/A

war

ds Applications Awards

Data provided by the Division of Information Services, Reporting Branch

0

10

20

30

40

50

60

70

NCI NIA NHLBI NCCAM

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Career Development Awards: Other mechanisms for support

Susan G. Komen Foundation: Career Catalyst Awardshttp://ww5.komen.org/researchgrants/grantprograms.html

American Cancer Society: Mentored Research Scholar Grantshttp://www.cancer.org/docroot/RES/RES_5_1.asp

Others: American Lung AssociationAmerican Heart AssociationCenters for Disease Control and Prevention

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Career Development Awards: 4 main parts to an NIH K-award app

1. Candidate statement2. Mentor letters3. Environment and institutional commitment to the candidate4. Research plan

3 sealed letters of recommendation, abstract, budget (modular) and justification, resources, biosketches, other support

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1. Candidate Statement

Candidate’s backgroundMake a compelling argument why you need a K award Be specific: give concrete examples of areas where you need additional training/experience in order to conduct the proposed research or meet research career goalsConvince reviewers that you are an outstanding candidate; include evidence of productivity (e.g. publications, presentations)

Career goals and objectivesshort- and long-term career goals

Career development planuniquely suited to youPropose a mix of didactic training (specific courses, individualized tutorials , etc.) and “hands on” research experienceThe research plan should include some specific “challenges,” for which you need additional training and experience to accomplishThese “deficits” are the focus of your career development plan

Training in the Responsible Conduct of Research

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2. Mentors Letters

Candidate’s description of mentorsPrimary area of researchMentoring track recordRelevance of mentor’s research to proposed training and/or researchMentor’s role in proposed training/researchInclude an evaluation component that describes how your mentors will assess your progress (e.g., quarterly meetings)

Primary mentor’s letterSenior investigator with a track-record of NIH funding Describes how the mentoring team will work togetherHis or her qualifications in the research proposed by the candidatePrevious experience as a research supervisorThe nature and extent of supervision that will occur

Co-mentors’ lettersA team of 2-3 additional mentors with complementary strengths, counter-balance any weaknesses Letters are shorter, but must be consistent with text in grant application (re: frequency of meetings, etc.).

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3. Environment and Institutional Commitment to the Candidate

Description of the institutional environmentResearch facilitiesEducational opportunities and relevance to career development plan

Institutional commitment: department chair’s letter

Confirm full-time faculty position during the K award period Protect at least 75% of effort for proposed research and career development activities

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New Investigator Awards: What are they?

Small amount of money ($30-100,000/yr) for risky, innovative, research with limited or no pilot data

New faculty (<5 years)

The intent is to help an investigator gather preliminary data necessary to pursue more developed studies (RO1-type grant application)

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New Investigator Awards: Mechanisms for support

UCLA JCCC: Seed Grantshttp://www.cancer.ucla.edu/index.aspx?page=165

UCLA AIDS Institute: Seed Grantshttp://www.uclaaidsinstitute.org/apply/apply.php

CHRP and CBCRP: IDEA Awardshttp://chrp.ucop.edu/applicants/appl_award_types.htmlhttp://www.cbcrp.org/apply/

DoD Congressionally Directed Medical Research Programs: Concept Awardshttp://cdmrp.army.mil/funding/default.htm

NIH: R-series (R21, R03, even RO1)http://grants.nih.gov/grants/new_investigators/index.htm

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New Investigator Award: 3 main parts to a CHRP IDEA app

1. New investigator justification

2. Responsive statement

3. Research plan*

Letter of Intent, Abstract (lay and scientific), budget and justification, resources, biosketches, other support

Part II: Research Plan

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Research Plan: Required components

A. Specific Aims and Hypotheses

B. Background

C. Preliminary Studies

D. Research Design and Methods

E. References

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Research Plan: Additional requirements for NIH grants

F. Protection of Human Subjects

G. Inclusion of Women and Minorities

H. Targeted/Planned Enrollment Table

I. Inclusion of Children

J. Vertebrate Animals

K. Select Agents

L. Consortium/Contractual Arrangements

M. Letters of Support

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Research Plan: Required components

A. Specific Aims and Hypotheses

B. Background

C. Preliminary Studies

D. Research Design and Methods

E. References

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RESEARCH DESIGN & METHODS

Addressing:

SPECIFIC AIMS

Supported by:

BACKGROUND & SIGNIFICANCE

PRELIMINARY STUDIES

Yang, Otto O. Guide to effective grant writing : how to write a successful NIH grant application

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Research Plan: Effort preparing versus reviewing

PREPARE REVIEWSpecific Aims 1% 9%Background 75% 1%Preliminary studies 9% 10%Research Design and Methods

15% 80%

Borrowed from Dr. Louise C Strong, U.T. M.D. Anderson Cancer Center

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Specific Aims

Focus, limit number of aims to 2-3Short and self-contained summary of the research questions and project goals Stand aloneThe success of one aim should not be dependent on the success of others

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Background

Provide a context for your work, make the case for why this research is important

Thorough but concise, include only pertinent information

End with a summary of current state of knowledge, what remains to be done, and highlight the innovation and significance of the proposed research

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Preliminary Studies

New investigators not expected to have a very elaborate preliminary studies section

A combination of your mentors’ research and your own experiences

Purpose: support the hypothesis

demonstrate previous experiences conducting similar research

showcase qualification of PI and mentors

Summarize importance at the end

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Research Design and Methods: Overview

A blueprint for the work to be performed

Due to limited funding, scope of the research plan needs to be appropriate

Piggy back project on mentor’s R01

For CDAs, the research plan is a training vehicle and should be well integrated with career development training plan

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Research Design and Methods: Methods details

Study designStudy populationDescription of specimens SNP Discovery/selectionLab methodsStatistical analysis Statistical powerTimelinePotential results and interpretationStrengths and limitations of approach

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Research Design and Methods: Common limitations

Multiple comparisons Can use a post-estimation false discovery adjustmentCan use an alpha less than 0.05 for power calculations

Sample size Power calculationsPropose follow-up studies

Population stratificationSubgroup analysesChoice of study designmatching on raceadjust for ancestral informative markers

Part III: Statistical Power

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False positive: Conclude that there is an association between E and D when there is not

α = Pr (Type I error) = level of statistical significance

False negative: Conclude that E and D are not associated when they truly are

β = Pr (Type II error)

Statistical power = 1 – β The probability that the null hypothesis will be rejected if it is indeed false

Statistical Power: Types of error

DECISION TRUTH

Ho is True Ho is False

Do not reject Ho Correct Type II error

Reject Ho Type I error Correct

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Statistical Power: Determinants

Sample size, exposure frequency, Type I error rate

Genetic model

Linkage disequilibrium

Genotyping error

Study design

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0.10 0.20 0.30 0.40 0.50

Minor allele frequencies

Recessive

1.0 1.5 2.0 2.50.0

0.2

0.4

0.6

0.8

1.0

Effect Size

Pow

er

Log-additive

1.0 1.5 2.0 2.50.0

0.2

0.4

0.6

0.8

1.0

Effect Size

Pow

er

300 cases, 300 controls, alpha=0.05

Statistical Power: Effects of genetic model and allele freq

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0.10 0.20 0.30 0.40 0.50

Minor allele frequencies

Recessive

1.0 1.5 2.0 2.50.0

0.2

0.4

0.6

0.8

1.0

Effect Size

Pow

er

Log-additive

1.0 1.5 2.0 2.50.0

0.2

0.4

0.6

0.8

1.0

Effect Size

Pow

er

300 cases, 300 controls, alpha=0.05

Statistical Power: Effects of genetic model and allele freq

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SNPs genotyped

SNPs not genotyped r2 Sample size requirement

S1 and S2 - - 600 600

S1 S2 1.00 600 600

S1 S2 0.85 600 706

N/r2 (Pritchard, 2001)

S1 S2

Statistical Model: Effects of linkage disequilibrium

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Statistical power: Effects of genotype error

Generally non-differential Reduces your power

Every 1% increase in genotyping error rates requires sample size increased by 2-8% (Zou et al, 2004, Genetic Epidemiology)

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Statistical Power: How to calculate

Calculate sample size for a given power and alpha, or power for a given sample size and alphaAlternative: minimum detectable OR for a given power, sample size, and alphaCalculators:

QuantoHtpowercc

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Quanto

http://hydra.usc.edu/GxE/Study design

Case-control (Matched or Unmatched)Case-onlyCase-siblingCase-parent trios Independent sample of individuals for quantitative traits

Genetic and environmental main effectsInteractions

Gene-geneGene-environment

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Table D.2. Minimum detectable odds ratios for a given allele/haplotype frequency (Po) & mode of inheritance (additive, dominant, and recessive)

All NHL N=220 ca/660 co

Non-CNS NHL N=154 ca/462 co

Non-CNS NHL, MACS only N=130 ca/390 co Po

Add Dom Rec Add Dom Rec Add Dom Rec 10% 1.59 1.67 >3.0 1.72 1.83 >3.0 1.80 1.92 >3.0 20% 1.44 1.56 2.42 1.54 1.69 2.78 1.59 1.77 2.98 30% 1.38 1.56 1.93 1.47 1.70 2.16 1.52 1.79 2.28 40% 1.36 1.61 1.72 1.45 1.78 1.89 1.50 1.88 1.98 50% 1.36 1.74 1.61 1.45 1.96 1.76 1.50 2.10 1.84

Table D.4. Minimum detectable interaction odds ratios for a given main effect, allele/haplotype frequency (Po) & mode of inheritance (additive, dominant, and recessive)

All NHL N=220 ca/660 co

Po Add Dom Rec

20% 1.71 2.27 >3.0

40% 1.55 2.90 >3.0