Transcript Research Questions/Objectives

DEPARTMENT OF PAEDIATRICS
Division of Rheumatology
Starting Your Project:
Background Information &
Objectives, Hypothesis
Residents/Fellows Clinical Research
Course 27th October 2015
Heinrike Schmeling
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 agency
Scientific/ethics board
• Own unique process and requirements
for proposals:
• Where the proposal will be submitted
• Limit of funding
• Obtaining detailed guidelines
Funding agency
Scientific/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
Study Problem
Relevance of Project
Informal Question
Literature Review
Research
No Hypothesis
(exploratory research)
/Objectives
Hypothesis
(explanatory research)
Study methods
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/Purpose
Example
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/Purpose
Example
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 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
Cellular pathway of methotrexate
Ranganathan et al, Arthritis Rheum 2006, 54: 1366-1377
MTHFR gene (C677T and A1298C) in RA
No. of
patients
Ethnicity
C677T
Efficacy
Toxicity

T
*JIA: 58
German
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

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

Not reported
A1298C
Efficacy
Toxicity
C

*Schmeling et al, J Rheumatol 2005, 32: 1832-1836
MTHFR gene (C677T and A1298C) in RA
No. of
patients
Ethnicity
C677T
Efficacy
Toxicity

T
*JIA: 58
German
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

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

Not reported
A1298C
Efficacy
Toxicity
C

*Schmeling et al, J Rheumatol 2005, 32: 1832-1836
MTHFR gene (C677T and A1298C) in RA
No. of
patients
Ethnicity
C677T
Efficacy
Toxicity

T
*JIA: 58
German
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

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

Not reported
A1298C
Efficacy
Toxicity
C

*Schmeling et al, J Rheumatol 2005, 32: 1832-1836
MTHFR gene (C677T and A1298C) in RA
No. of
patients
Ethnicity
C677T
Efficacy
Toxicity

T
*JIA: 58
German
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

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

Not reported
A1298C
Efficacy
Toxicity
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/Objectives
Example
This proposal is aimed at characterizing
gene variants underlying variability in
methotrexate toxicity and efficacy in
juvenile idiopathic arthritis (JIA).
Pilot study: example
…….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
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” Hypothesis
Null 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 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 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?
• Questionnaires/Surveys
• Observational
• Cross sectional
• Case control/cohort
• Clinical trial
• Systematic review/ metaanalysis
Study subjects?
• Inclusion/exclusion criteria
• How to recruit (where?, enough?)
Variables?
• Predictor/outcome
Sample size?
The 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 searching
Literature searching
How I get my informations?
What I am looking for?
•
•
•
•
•
expert
books
review
metaanalysis
original article
Literature searching
• Used to be very difficult
Index 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: 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
Ovid
www.ncbi.nlm.nih.gov/sites/entrez
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 searching
What I am looking for?
•
•
•
•
population
disease
predictor/outcome
relevant topics
e.g. statistic methods
Evidence-based medicine
Evidence-based medicine
Quality 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