Residents/Fellows Clinical Research Course 27 th October 2015 Heinrike Schmeling DEPARTMENT OF...
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Transcript of 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