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Title: Designing Clinical Research A course for pre-doctoral researchers January 4-March 8, 2007 Winter Quarter


1
Designing Clinical Research A course for
pre-doctoral researchersJanuary 4-March 8,
2007Winter Quarter
  • UC San Francisco School of Medicine

2
Thomas E. Novotny, MD, MPHJanuary 4, 2007
Course overview

3
Faculty and staff Dept. of Epid. and Biostat.
Name Role
Thomas E. Novotny, MD MPH Co-Director/group leader
Nancy Lane, MD Co-Director/group leader
Olivia de Leon Course Support
Allison Deneen Website Management and Communications
4
Course Objectives
  • Acquire research skills
  • Produce a 5-page protocol for a real study
  • Help others in the course (peer review)
  • Provide feedback on the course
  • Have a multiplier effect

5
Types of Study
  • Not the best choice for this course
  • Mice, molecules
  • Cost-effectiveness, meta-analysis
  • Secondary data analysis
  • Qualitative research
  • Ideal
  • A new observational study (or experiment)
    involving humans that you will do this year

6
Structure of the course
  • 10 weeks in length, Thursdays 4-7 PM
  • Lecture 4-530 PM, break with sandwiches
  • Small group 530-700 PM
  • One excused absence permitted (attendance taken)
  • Assigned readings writing sections to be
    completed by Monday at 5 PM, sent to group leader
    by email
  • Discuss the various sections of each others
    protocols in small groups each week
  • Full protocol Due Noon, March 2 to Olivia by
    email (olivia_at_epi.ucsf.edu)
  • Peer Review Thursday, March 8, 4-530 followed by
    evaluation and dinner meeting of John Snow
    Society at Kezar Pub

7
Additional Course Essentials
  • On-line CHR Course prior to ethics lecture on
    January 25
  • https//www.researchonline.ucsf.edu/
  • EndNote Classes in Library
  • Designing Clinical Research, 3rd Edition, Hulley
    et al.

8
The research question Thomas E. Novotny, M.D.,
M.P.H.January 4, 2007
Lecture 1 Designing Clinical Research for
Pre-doctoral researchers

9
Sections of the study protocol
  • Research question
  • Significance (background)
  • Study design
  • Study population and sampling
  • Variables and measurements
  • Statistical issues
  • Ethical issues
  • Quality control and data management

10
The research question
  • All studies should start with a research question
    that addresses what the investigator would like
    to know
  • Goal is to find an important research question
    that can be developed into a feasible and valid
    study plan

11
The research cycle
Develop research question
12
The research cycle
Develop research question
Design study
13
The research cycle
Develop research question
Design study
Implement study
14
The research cycle
Develop research question
Design study
Implement study
Analyze results
15
The research cycle
Develop research question
Infer conclusions
Design study
Implement study
Analyze results
16
The research cycle
Develop research question
Infer conclusions
Design study
Implement study
Analyze results
17
The research question
  • Format for descriptive study
  • In a population of study population, what is
    the prevalence (or mean, median, etc.) of
    outcome variable?
  • Most studies will have more than one research
    question
  • The research protocol flows from the research
    question

18
The research question
  • Usual format (analytic studies)
  • In a population of study population, is
    predictor variable associated with outcome
    variable?

19
Examples of research questions
  • In a population of injection drug users with HIV
    infection, is HAART use associated with fewer
    opportunistic infections?
  • In a population of HIV-infected Croatian patients
    on HAART, is a Mediterranean diet associated with
    lower risk of dyslipidemia?
  • In a population of Croatian merchant seaman, is
    unprotected sex with sex workers in African ports
    associated with HIV infection?

20
What is the research question in this abstract?
  • Acute respiratory tract infections caused by
    Streptococcus pneumoniae are a leading cause of
    morbidity and mortality in young children. We
    evaluated the efficacy of a 9-valent pneumococcal
    conjugate vaccine in a randomized, double-blind
    study in Soweto, South Africa. At 6, 10 and 14
    weeks of age, 19,922 children received the
    9-valent pneumococcal polysaccharide vaccine
    conjugated to a noncatalytic cross-reacting
    mutant of diphtheria toxin (CRM197), and 19,914
    received placebo
  • Klugman KP, Madhi SA, Huebner RE, et al. A trial
    of 9-valent pneumococcal conjugate vaccine in
    children with and without HIV infection.
  • N Engl J Med 2003 3491341-8.

21

In a population of study population is
predictor variable associated with outcome
variable?
  • In a population of South African infants is
    immunization with a 9-valent pneumococcal
    conjugate vaccine associated with invasive
    pneumococcal disease?

22
Origins of a research question
  • Mastering the literature
  • Scholarship -- be a scholar and know the
    literature
  • Get a mentor
  • Be alert to new ideas and techniques
  • Importance of teaching
  • Be imaginative

23
FINER characteristics
  • Feasible
  • Interesting to the investigator
  • Novel
  • Ethical
  • Relevant

24
FINER characteristicsCriteria for feasibility
  • Adequate number of subjects
  • Adequate technical expertise
  • Affordable in time and money
  • Manageable in scope

25
FINER characteristicsCriteria for novelty
  • Confirms or refutes previous findings
  • Extends previous findings
  • Provides new findings

26
FINER characteristicsCriteria for relevance
  • To scientific knowledge
  • To clinic, public health or health policy
  • To future research directions

27
Problems and solutionsResearch plan is not FINER
  • Not feasible
  • Too broad
  • Not enough subjects available
  • Methods beyond skill of investigator
  • Too expensive
  • Not interesting, novel or relevant
  • Uncertain ethical suitability

28
Problems and solutionsResearch plan is not
feasible
  • Too broad
  • Smaller set of variables
  • Narrow the question
  • Not enough subjects available
  • Expand inclusion criteria
  • Modify exclusion criteria
  • Add other sources of subjects
  • Lengthen the time frame for entry into study
  • Use strategies to decrease sample size

29
Problems and solutionsResearch plan is not
feasible
  • Methods beyond skill of investigator
  • Collaborate with colleagues who have skills
  • Consult experts and review literature for
    alternative methods
  • Learn the needed skills yourself
  • Too expensive
  • Consider less costly study design
  • Fewer subjects and measurements
  • Less extensive measurement
  • Fewer follow-up visits

30
Problems and solutionsResearch plan is not FINER
  • Not interesting, novel or relevant
  • Consult with mentor
  • Modify the research question
  • Uncertain ethical suitability
  • Consult with institutional review board (ethics
    committee)
  • Modify the research question

31
Problems and solutions
  • Study plan is vague
  • Write the research plan at an early stage
  • Get specific in the 1 to 2-page study plan
  • How the subjects will be sampled
  • How the variables will be measured

32
Problems and solutions examples
  • What is the relationship between depression and
    health?
  • Does eating red meat cause cancer?
  • Does lowering serum cholesterol prevent heart
    disease?
  • Do contraceptive vaginal sponges prevent HIV
    infection?

33
Anatomy of Clinical Research
34
Physiology of clinical research How it works
  • Using measurements in a sample
  • to draw inferences about
  • Phenomena (variables) in a population

35
Types of variables
Predictor
Outcome
Generally categorized as exposures
36
The research question
  • In descriptive studies
  • In a population of study population, what is
    the prevalence of outcome variable?
  • In analytic studies
  • In a population of study population, is
    predictor variable associated with outcome
    variable?

37
Types of clinical studies
  • Studies with no variables
  • Case studies, case series, editorials, opinions,
    reviews
  • Studies with single variables
  • Descriptive studies and surveys
  • Studies with 2 variables
  • Experiments
  • Observational studies
  • Meta-analyses and systematic reviews

38
Hierarchy of clinical study types
39
Variables
Predictor variable (independent)
Outcome variable (dependent)
40
Hulleys Research Question (1993)
  • Should postmenopausal women receive hormones?

41
Hulleys Research Question (1993)
  • Should postmenopausal women receive hormones?
  • Subjects postmenopausal women
  • Predictor hormones
  • Outcome ?

42
Improved Research Question
  • Does estrogen treatment prevent
  • heart attacks in postmenopausal women?
  • Subjects postmenopausal women
  • Predictor estrogen treatment vs none
  • Outcome heart attacks

43
FINER?
  • Feasible
  • Interesting
  • Novel
  • Ethical
  • Relevant

44
Need to specify design
  • Observational study
  • Cross-sectional
  • Case control
  • Cohort
  • Randomized clinical trial
  • Surrogate endpoints
  • Endpoints of primary interest

45
Cohort design
  • Subjects
  • 5000 women age 55 living in the Bay Area
  • Predictor
  • Taking post-menopausal estrogen at baseline?
  • Outcome
  • Subsequent 5-year incidence of heart attacks

46
Cross-sectional design
  • Subjects
  • 2000 women age 55 seen at SFGH
  • Predictor
  • Taking post-menopausal estrogen?
  • Outcome
  • History of heart attack?

47
Case-control design
  • Subjects
  • Cases 100 women with heart attacks in the SFGH
    ED
  • Controls 100 women with trauma in the SFGH ED
  • Predictor
  • Taking post-menopausal estrogen?
  • Outcome
  • Cases vs controls

48
Ethical?
  • Equipoise (uncertain whether benefits or harms
    predominate)
  • Benefits of hormone Rx
  • Reduce menopausal symptoms
  • ? Prevent fractures
  • ? Prevent CHD
  • ? Prevent Alzheimers Disease
  • ? Improve quality of life
  • Harms
  • ?Venous thrombo-embolism
  • ? Breast cancer

49
Relevant?
  • Premarin/Prempro 1 in sales
  • Decision faced by half the population

50
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51
Making a research plan
  • Define the research question
  • Develop the research plan
  • List the elements of the study
  • Identify published references on your question
  • Write a background and significance section
    (history of previous work, rationale, importance)
  • 4. SOCO...single, over-riding communication
    objective.

52
Study plan
  • Research question
  • Significance (background)
  • Study design
  • Study population and sampling
  • Variables and measurements
  • Statistical issues
  • Ethical issues
  • Quality control and data management
  • What is the focus of the study?
  • Why is it important?
  • How will you study it?
  • Who are the research subjects and how are you
    going to select them?
  • What measures will be done?
  • What will the size of the study be and how will
    you analyze it?
  • Are there ethical issues?
  • How will the study be managed to assure high
    quality results?

53
Background and significance
  • Build on experience
  • Be alert to new ideas
  • Be alert to new technologies
  • Be knowledgeable about the strengths and
    limitations of earlier research
  • Know what you want to communicate at the end

54
Developing background and significance section
for a protocol
  • Same role as introduction in a paper
  • Puts the research question in context
  • Describes the rationale for the study
  • What is known about the topic to be studied
  • Why is the research question important?
  • What type of answer will be the study supply?

55
Background and significance
  • Cites previous research that is relevant
    (including the investigators own work)
  • Indicates the strengths and weakness (or
    problems) of previous studies and what questions
    remain unanswered
  • Be clear how the results of the proposed studies
    will help lead to resolution of uncertainty and
    influence public health policy or clinical
    practice

56
Finding pertinent literature
  • Use End Note or a similar program
  • Check format of references from journals
    instructions to authors and include them as you
    write protocol
  • Keep copies of all references handy
  • Search PubMed
  • Personal communications (who and when)
  • Unpublished data (best to avoid)

57
Examples from students
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