residents/fellows clinical research course 27 th october 2015 heinrike schmeling department of...

Residents/Fellows Clinical Research Course 27th October 2015

Heinrike Schmeling

DEPARTMENT OF PAEDIATRICS Division of Rheumatology

Starting Your Project:Background Information &

Objectives, Hypothesis

Outline • Starting your project - How to write a proposal 

• How to plan/proceed• Introduction/literature review• Research question/objectives/hypothesis• Methods• Significance

 • Literature searching - databases

Starting your project…….

Why to write a research proposal

• Self-learning/”brain storming”• Study plan

• Organize• Clarify• Refine all elements of the study

• Funding• Science/ethics approval

Funding agencyScientific/ethics board

• Own unique process and requirements for proposals:

• Where the proposal will be submitted• Limit of funding• Obtaining detailed guidelines

Funding agencyScientific/ethics board

• Own unique process and requirements for proposals:

• Where the proposal will be submitted• Limit of funding• Obtaining detailed guidelines

How to plan/proceed

• Checklist: what do I need? (Team?)• Timeline/timetable• Short outline of your proposal• Find a model proposal• Meet periodically with your supervisor

• Be punctual• Be prepared• Be responsible

Review, pretest, and revise repeatedly……

Research proposals are intended to demonstrate

• That your project should be done• Specifically what you intend to accomplish

and how you will do it• Work plan that demonstrates you have though

through all of the elements of your project

Potential audience!

Oberservation/Idea

Informal Question

Study Problem

Relevance of Project

Study methods

Literature Review

No Hypothesis(exploratory research)

Hypothesis(explanatory research)

Justification of research

• Why we are doing this study?• Why is this research important? • Why this way• Are there gaps in the literature?• Would the answers have clinical value?

Study Title

• Informative, succinct, interesting• First impression• Reminder: content/design of the study

• Include:• Population of interest• Condition/issue being investigated

Study Title

• Common pitfalls:• Too brief /too long• Incorrect terminology• Not specifying the population of

interest

Study Title: example

“Pharmacogenetics of Juvenile Idiopathic Arthritis and Juvenile Dermatomyositis: A

genome wide association study on treatment efficacy and toxicity”

Study Problem/Purpose

• A broad statement indicating the goals of the project (abstract,summary, overview)

• Research question/rational• Design/methods• Statement of the importance of potential findings

Must stand on its own!

Study Problem/Purpose

• Keys to success:

• Relevant• Clear• Logically argued

Study Problem/PurposeExample

Juvenile idiopathic arthritis (JIA) and juvenile dermatomyositis (JDM) are chronic inflammatory diseases of childhood. The majority of children continue to require treatment many years after diagnosis.

However, 30% to 50% of patients do not have a complete response to immunosuppressive treatments and some children develop significant side effects.

There are no useful and reliable clinical, biological or molecular markers that predict response to therapy.”

Study Problem/PurposeExample

This research focuses on identifying key gene variants that predict response to immunosupressive therapy and treatment-related toxicity.

Discovery of a predictive clinical-biological pharmacogenetic model

that will enable “individualized therapy”

may have important impact in making treatment decisions and ultimately on improving personalized patient care, outcomes, quality of life and health.

Background informationBackground information

Relevance/Study Rationale

• Why should the research be done

• Why is the research important• Has it been done before• Will the study benefit patients, increase

knowledge and/or influence policy• Will reseach resolve controversies• Would the answers have clinical value

Relevance/Study Rationale

• Keys to success:• Lead reviewers to answer the

questions• Should be reasonable given the

proposed study? • Justification by literature review• Priority areas of granting agencies: be

sure to explain how your study fits into those areas

Literature Review

• Critical summary of research• Put a research problem in context• Identify gaps /weaknesses in prior

studies so as to justify a new investigation

• if little known, look at related information• adult rather than paediatric• other diseases• animal data• broader class of information

Literature Review

• Starts off broadly addressing the problem then becoming more narrow and leading

• Example: • JIA is a chronic inflammatory

disease…..

Literature Review

• Key to success:• Identify gaps in knowledge or

controversies• Focused on and leading naturaly to

your research questions/objectives• Be thorough, relevant, and up-to-date• Use primary sources of original

research• Synthesize and be critical• Provide local background

Ranganathan et al, Arthritis Rheum 2006, 54: 1366-1377

Cellular pathway of methotrexate

MTHFR gene (C677T and A1298C) in RANo. of patients Ethnicity C677T

Efficacy ToxicityA1298C

Efficacy Toxicity

*JIA: 58 German T C

71 Netherland T Not done Not done

236 Netherland T Not done Not done

309 UK T

115 Japan

93 Israel CC

106 Japan T C

98 Australia Not reported Not reported

48 USA T C

174 Poland T Not reported C Not reported

95 USA (CA, AF) Not reported Not reported

150 India Not done Not done

85 China Not reported Not done Not done

34 India (Asian)

223 USA (CA, AF) A CA n=193

213 Slovenia CC

205 Netherland CC AA C

214 USA Not reported TT Not done Not done

159 Japan T C

*Schmeling et al, J Rheumatol 2005, 32: 1832-1836

MTHFR gene (C677T and A1298C) in RANo. of patients Ethnicity C677T

Efficacy ToxicityA1298C

Efficacy Toxicity

*JIA: 58 German T C

71 Netherland T Not done Not done

236 Netherland T Not done Not done

309 UK T

115 Japan

93 Israel CC

106 Japan T C

98 Australia Not reported Not reported

48 USA T C

174 Poland T Not reported C Not reported

95 USA (CA, AF) Not reported Not reported

150 India Not done Not done

85 China Not reported Not done Not done

34 India (Asian)

223 USA (CA, AF) A CA n=193

213 Slovenia CC

205 Netherland CC AA C

214 USA Not reported TT Not done Not done

159 Japan T C

*Schmeling et al, J Rheumatol 2005, 32: 1832-1836

MTHFR gene (C677T and A1298C) in RANo. of patients Ethnicity C677T

Efficacy ToxicityA1298C

Efficacy Toxicity

*JIA: 58 German T C

71 Netherland T Not done Not done

236 Netherland T Not done Not done

309 UK T

115 Japan

93 Israel CC

106 Japan T C

98 Australia Not reported Not reported

48 USA T C

174 Poland T Not reported C Not reported

95 USA (CA, AF) Not reported Not reported

150 India Not done Not done

85 China Not reported Not done Not done

34 India (Asian)

223 USA (CA, AF) A CA n=193

213 Slovenia CC

205 Netherland CC AA C

214 USA Not reported TT Not done Not done

159 Japan T C

*Schmeling et al, J Rheumatol 2005, 32: 1832-1836

MTHFR gene (C677T and A1298C) in RANo. of patients Ethnicity C677T

Efficacy ToxicityA1298C

Efficacy Toxicity

*JIA: 58 German T C

71 Netherland T Not done Not done

236 Netherland T Not done Not done

309 UK T

115 Japan

93 Israel CC

106 Japan T C

98 Australia Not reported Not reported

48 USA T C

174 Poland T Not reported C Not reported

95 USA (CA, AF) Not reported Not reported

150 India Not done Not done

85 China Not reported Not done Not done

34 India (Asian)

223 USA (CA, AF) A CA n=193

213 Slovenia CC

205 Netherland CC AA C

214 USA Not reported TT Not done Not done

159 Japan T C

*Schmeling et al, J Rheumatol 2005, 32: 1832-1836

This is your chance to build a case for doing your study!

Research Questions/Objectives

The research question is the objective of the study

A good research question should be: • Feasible (time, funding, population etc)• Interesting• Novel• Ethical• Relevant

Research Questions/Objectives

• Explicitly state what you propose to study

• Form the foundation for the rest of the proposal

• Will be used to assess the adequacy/appropriateness of the study’s proposed methods• Testable• Logically derived from the literature

review

Research Questions/Objectives

• Often includes:• Population of interest • Variables (independent/dependent)• Relationship between variables

being investigated

Research Questions/Objectives

• Key to success:• Be clear and consistent• Only one or two primary research objectives• Include indepent/dependent variables• Objectives must be measurable• Objectives relevant or novel• If it is a pilot study, state clearly the pilot objectives

Research Questions/ObjectivesExample

This proposal is aimed at characterizing gene variants underlying variability in methotrexate toxicity and efficacy in juvenile idiopathic arthritis (JIA).

…….We need to demonstrate the feasibility of an approach prior to proposing a definitive large-scale study.  

Pilot study: example

 Therefore our primary pilot research questions are: 1. Can we accrue over 80% of our targeted sample into a genetic substudy? 2. What are the barriers to successful collection and shipment of salivary DNA samples to the central laboratory? 3. What are the barriers to successful DNA extraction and genotyping from collected samples? 4. In order to plan further studies, what is the estimated effect size/ risk ratio associated with the chosen polymorphisms? 

Pilot study: example

Our overall research program will answer these questions: 1. Do specific single nucleotide polymorphisms in selected genes predict the response to MTX and the potential side effects from MTX in our cohort? 2. Do genetic variants in combination with other genes confer increased efficacy and susceptibility to toxicity of MTX therapy in our cohort?3. Can we create a predictive profile for each patient that will enable “individualized therapy” and may therefore help in maximizing the benefit:risk ratio of MTX-therapy

Pilot study: example

Hypothesis

Specific version of the research question that summarize the main elements of the study

• sample• predictor• outcome variables

in a form that establishes the basis for tests of statistical significance

Hypothesis

Needed for studies that will use tests of statistical significance to compare findings among groups

• based on a good research question• simple• specific• a priori• stated in advance 

Simple Hypothesis

• one predictor – one outcome variable

„ a sedentary lifestyle is associated with an increased risk of proteinuria in diabetes“

Complex Hypothesis

• more than one predictor variable

„a sedentary lifestyle and alcohol cosumption are associated with an increased risk of proteinuria in diabetes“

• more than one outcome variable

„alcohol cosumption is associated with an increased risk of proteinuria and nephropathy in diabetes“

Hypothesis: example

We hypothesize that, in JIA patients treated with MTX, genetic variants are associated with treatment outcome and toxicity  

The “Null” HypothesisThe “Null” Hypothesis

Null HypothesisNull Hypothesis

no association

between the predictor and outcome variables

• Development of new AIDS drug……..

• Null hypothesis:

The new drug is no better than the existing drug

Alternative HypothesisAlternative Hypothesis

association

between the predictor and outcome variables

• Alternative hypothesis:

The new drug is better than the existing drug

• One sided: specifies the direction of the association

• Two sided: states only that an association exists, its

does not specify the direction

NIH Hypothesis ChecklistNIH Hypothesis Checklist

• Is my proposal driven by a strong hypothesis? • Have I defined what, specifically, I am setting out to prove? • Is the central research question important to the field? • Is the hypothesis testable by current methods? • Did I state my hypothesis in the abstract and specific aims

section? • Is my idea focused enough? Is it provable during my three-

to four-year award with the resources I am requesting? • Does my topic fit with the NIH mission? Does it work

towards improving health through science?

Study design?Study design?

• Questionnaires/Surveys

• Observational

• Cross sectional

• Case control/cohort

• Clinical trial

• Systematic review/ metaanalysis

Study subjects?Study subjects?

Variables?Variables?

• Inclusion/exclusion criteria

• How to recruit (where?, enough?)

Sample size?Sample size?

• Predictor/outcome

The scientific methodThe scientific method

• Propose a hypothesis

• Design an experiment to test the hypothesis

• Collect data that will test the hypothesis

• Draw conclusions

• Repeat as necessary!

Literature searchingLiterature searching

Literature searchingLiterature searching

How I get my informations?What I am looking for?

• expert• books• review• metaanalysis • original article

Literature searchingLiterature searching

• Used to be very difficultIndex Medicus - Since 1879 (last Dec 2004)

• Now electronic databases– MEDLINE:

compiled by US National Library of Medicine/Institutes of Health“The world's most comprehensive source of life sciences and biomedical bibliographic information, with over twenty million records”

NCBI: NCBI: National Center for Biotechnology Information

• advances science and health by providing free access to biomedical and genomic information

• houses: GenBank

OMIM

Pubmed Central etc etc

Pubmed www.ncbi.nlm.nih.gov/sites/entrez Ovid http://ovidsp.ovid.com/

OVID v PubMed

• Access the same database

• Choice?– Matter of style?– What you used first?– Like a MAC v PC??

• Both easily accessible (anywhere)

Cochrane Collaboration/Database

• International, independent, not-for-profit• Systematic reviews of the effects of healthcare practice, including complete reviews and protocols for reviews currently being prepared• intended to help make informed decisions about health care• most comprehensive, reliable and relevant source of evidence on which to base these decisions.

EMBASE: Experpta Medica

three separate databases: (1)EMBASE: Excerpta Medica Database (2)EMBASE Drugs and Pharmacology (3)EMBASE Psychiatry.

•Major biomedical and pharmaceutical database indexing over 3,500 international journals. Approx. 375,000 records added yearly.

• Coverage is from 1980 to the present.

Up to date

A practical clinical reference, contains the equivalent of 40,000 pages of original, peer-reviewed text which provides specific, practical recommendations for diagnosis and treatment.

• for clinicians• for patients• patient informations

Keyword searchingKeyword searching

What I am looking for?

• population• disease• predictor/outcome• relevant topics

e.g. statistic methods

Evidence-based medicine

Evidence-based medicineQuality of evidence

Level I:

Level II:

Level III:

Evidence-based medicine

Endnote

reference management software

• Search bibliographic databases on the internet• Organize references, images, PDFs and other files• Watch the bibliography and figure list appear as you write

Take Home Messages

"Learn from yesterday, live for today, hope for tomorrow. The important thing is not to stop questioning.”

Albert Einstein