Teaching Registrars Research Methods Study design

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Teaching Registrars Research Methods Study design

• Landon Myer PhD
• Senior Lecturer, Infectious Diseases Epidemiology
  Unit, School of Public Health, UCT
• lmyer_at_cormack.uct.ac.za

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Orientation to todays session

• So far
• Introduction
• Study protocol
• Reviewing the Literature
• Today ? Study design ?
• To come
• Sampling
• Measurement
• Data analysis
• Ethics

All of one interrelated process
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Overview

• How to start to select a study design
• Framework for considering different study designs
• Key similarities differences
• Introduction to each major category of study
  design
• Focus on major functional features
• Strengths limitations
• Examples
• Exercises

Ask questions throughout!
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Note on terminology

• Outcomes
• Health outcome of interest in the study
• Disease, death, side effect, complication
• (stats dependent variables)
• Exposures
• Measures that may be associated with the outcome
• Possible risk factors, causes, determinants
  
• (stats independent variables)

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I. Framework for thinking about study designs
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What are study designs?

• Structured approaches to address specific
  research questions
• Provide general guidelines for thinking about
  specific aspects of study conduct
• sampling populations
• systematically collecting measurements
• analysing data
• Strengths limitations of specific designs are
  well-established

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How to select a study design

• Start with a good study question
• Relevant
• Addresses topic of significance to health of
  local population / health care services
• Novel
• Makes meaningful contribution to existing
  knowledge new insights
• Feasible
• Not overly ambitious

Creativity
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Different types of study questions lead to
different types of study designs

• Descriptive
• What is the prevalence of condition Z in a
  specific population?
• Analytic
• What are the factors associated condition Z? Is
  condition X a risk factor for condition Z?
• Diagnostic
• How good is test Q in detecting condition Z?

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Selecting the right study design option

• Relevant
• Design allows you to answer your research
  question
• Novel
• Design allows meaningful contribution to existing
  knowledge new insights
• Feasible
• Design allows study to be done within available
  time and funds
• Simple
• ALWAYS avoid ALL unnecessary complexities

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Types of study designs

• Many types
• Most are some variation on general themes
  presented here
• All designs based on same basic principles
• key differences in how study design samples
  participants with respect to
• exposures (risk factors, patient
  characteristics)
• outcomes (diseases, conditions)

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Choice of study design closely related to other
aspects of protocol

• Study design choices inform how you will sample a
  specific study population
• in a way that its understood how the participants
  in the study relate to the population in general
• 2. Study design choices inform the most
  appropriate measurements to collect on
  participants in a standardised manner (create
  data)

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• 3. Study designs will point to the most
  appropriate analysis of data to answer study
  question
• Descriptive
• Calculate the proportion of the study population
  with condition Z (incident or prevalent)
• Analytic
• Compare the frequency of condition Z among groups
  of the population
• Diagnostic
• Calculate the validity (sensitivity/specificity)
  or reliability of test Q in detecting condition Z

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Broad categories of options in study design

• Cross-sectional
• Case report / case series
• Case-control
• Cohort
• Randomised Controlled Trial (RCT)

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Broad categories of options in study design

• Cross-sectional
• Case series
• Case-control
• Cohort
• Randomised Controlled Trial

Diagnostic
?
Descriptive
Analytic
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Broad categories of options in study design

• Cross-sectional
• Case report/series
• Case-control
• Cohort
• RCT

Observational designs investigator is only
observing distribution of variables (risk
factors, diseases, etc) in nature
Experimental designs investigator assigns study
conditions usually testing an intervention
(many variations here)
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Key differences between study designs

• How participants are sampled
• Are participants sampled according to exposure
  status, disease status, neither, both?
• When measurements are taken
• Are some variables measured before others, or are
  measurements taken all at once?
• How outcome variables are measured
• Incident or prevalent outcomes (morb/mort)?
• Are there comparison groups involved?
• Is design observational or experimental?

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Time marches on

• Onset of conditions takes place over time in
  populations
• Different study designs deal with the onset of
  conditions through time in different ways
• Critical to understand how your choice of study
  design handles the timing of
• Identification of participants
• Measurement of variables (exposure, disease)

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X onset of condition of interest
1
X
Died
2
Died
3
4
5
X
Died
6
7
X
8
X
Died
9
X
10
X
Died
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Time
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II. Details on categories of study designs

• Case report case series
• Case-control
• Cross-sectional
• Cohort
• RCT other experimental designs

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Case-report case-series

• Cases
• people with health outcome
• depends on what is of interest
• Case report / series
• Describes
• characteristics of disease / condition
• characteristics of individual that may be
  associated with the condition

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Issues in case-only designs

• Useful for descriptive purposes only
• Implicit comparisions to what is expected or
  normal
• Why might this be problematic?

vs
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Case-control studies

• Set of cases (usually from health service)
• Comparable set of controls (various sources)
• Both groups evaluated on characteristics /
  exposures of interest
• Compare distribution of exposure in cases and
  controls

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Exposed
Cases
Unexposed
Exposed
Controls
Unexposed
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Exposed
Cases
Unexposed
Exposed
Controls
Unexposed
Time
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Example Does childrens inhalation of hairspray
facilitates development of asthma?

• 50 new cases of severe asthma identified at RXH
  in 12-month period, all lt5 yrs of age
• These cases are compared to
• 90 children lt5 years attending
• RXH for orthopedic surgery
• (who do not have asthma)
• Cases and controls are
• compared on maternal hairspray
• use since childs birth

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Hairspray
Children with asthma
No hairspray
Hairspray
Children without asthma
No hairspray
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Odds ratio in 2x2 table

• Odds ratio (A/C) / (B/D)

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Strengths limitations of case-control study

• Relatively simple quick approach to address
  analytic questions
• Ideal to study rare diseases (vs cohort)
• Cases potential controls are accessible in
  health care setting
• Choice of the wrong control group selection
  bias
• Cases may over-report past exposures
  information bias

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Cross-sectional studies

• Most common form of research surveys
• Measure all variables on participants at same
  point in time (approximately)
• Measure prevalent disease (not incidence)

X Disease
X Exposure
Time
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Defined population
Sampling
Collect data on outcome (disease) and exposure
(risk factors)
Exposed Diseased
Exposed Not diseased
Not exposed Diseased
Not exposed Not Diseased
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Example How severe is disease among rheumatoid
arthritis patients attending GSH?

• Study population patients attending rheumatology
  clinic at GSH during one month period
• Measures degree of disease severity (outcome)
  demographics, disease history, treatment history
  (exposures)
• Analysis prevalence of severe disease in clinic
  population association between severity of
  disease and different exposures

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Benefits of cross-sectional study

• Feasibility ? easy to do
• In health care setting, can work from existing
  records (consent issues)
• Low cost, rapid
• Not waiting for incident outcomes to develop
• Can calculate prevalence
• Often most relevant measure for burden of
  disease, informing health care strategies
• Measure of association calculate Odds Ratio for
  prevalent disease

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Issues in cross-sectional studies

• Measuring prevalent disease only
• Prevalence incorporates incidence of disease AND
  duration of disease
• Risk factors for prevalent disease often
  different from risk factors for incident disease
• Issues of timing (temporality) are a problem
• Exactly when did disease develop?
• Did exposures come before or after onset of
  disease?

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Cohort studies

• Start with group of individuals without the
  outcome of interest at risk
• Follow forward in time to observe incidence of
  disease (a rate)
• Can be descriptive or analytic
• If analytic question, then measure exposures on
  cohort at the beginning of the study

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Cohort studies can be purely descriptiveEg
What is the rate of remission among men treated
for prostate cancer at GSH?
Develop outcome of interest
At risk participants (without outcome)
Do not develop outcome of interest
Time
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Analytic cohort studyEg Do ß-blockers increase
risk of renal transplant rejection?
Develop the outcome of interest
Exposure
Study population without the outcome of interest
Do not develop the outcome of interest
Develop the outcome of interest
No exposure
Do not develop outcome of interest
Time
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Types of cohort studies

• Prospective
• Following cohort forward through time from
  present
• Most common approach
• Retrospective
• Assemble cohort from medical records,
• follow based on records
• Follow-up is in the past (can extend into present)

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Measure of association in a cohort study
relative risk (aka risk ratio, rate ratio)
New cases of outcome
Participants who do not develop outcome
A
B
Exposed
Total number of exposed A B
D
C
Unexposed
Total number of unexposed C D
Total number of participants A B C D
RR A/(AB) / C/(CD)
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Strengths problems in cohort studies

• Strengths
• Can calcluate rates of new events valuable
• Timing of exposure before disease assured
• Good for studying health effects of rare
  exposures (can select an exposed cohort)
• Weaknesses
• Participants self-select their exposure status
  leads to confounding, bias
• Take time, resources (if prospective)
• Many subjects needed for rare outcomes

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Randomised controlled trials

• Principal experimental design in medical research
• Like a cohort study, except exposure status is
  assigned by investigator (randomly) not just
  observed
• Complex, take time ? costly
• RCTs are usually best design for testing the
  impact of a specific intervention in improving a
  specific health outcome

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Have outcome of interest
Exposure
Study population without the outcome of interest
Do not develop outcome of interest
Randomisation
Have outcome of interest
No exposure
Do not develop outcome of interest
Time
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Key features of RCT

• Randomisation
• Removes selection bias or confounding
• Alternation or other assignment schemes are bad
  idea
• Use of concurrent control groups
• Vs Before/After studies
• Blinding whenever possible
• Blind investigators prevents information biases
• Blind participants prevents selective behaviour
  change during the trial
• Not just in trials

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• RCTs are important tools
• But can encounter major problems that hinder
  interpretation of results
• Generalizability Trial participants are highly
  selected individuals
• often not representative of general population at
  risk
• Complexity Trials procedures can be complex (and
  costly)
• when key design features breakdown, the
  experiment is compromised

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Other experimental designs

• For an experiment, need to compare 2 states with
  intervention vs without
• Before/after studies

Introduction of Pfizer fluconazole donation
programme at GFJ
Median survival of cryptococcal meningitis in
HIV before
Median survival of cryptococcal meningitis in
HIV after
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• Controlled before/after studies

BEFORE
AFTER
New training in sterile procedures
MMH intervention
Rate of postoperative sepsis
Rate of postoperative sepsis
vs
No new training
NSH control
Rate of postoperative sepsis
Rate of postoperative sepsis
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• Time-series studies

Rate of advanced cervical cancer cases per 100,000
of pap smears performed in Western Cape
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III. Conclusion
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The hierarchy of study designs

• Frequently see framework for comparing evidence
  based on the study design used
• RCT / experiments
• Cohort
• Case-control
• Cross-sectional
• Case series/report

better evidence more valid
worse evidence less valid
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Not (nearly) so simple

• The study design alone does not make the evidence
  from a study better or worse
• The details of how a study is conducted is what
  matters
• Rigour in design, sampling, measurements,
  analysis
• This is why the Methods section is the most
  important part of scientific papers

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Wrap-up

• Framework for thinking about study designs when
  developing research ideas for MMed
• Start with a good research question
• Understand different study design options
• Select the most feasible study design based on
  the study question
• Balance time, funding, available data sources
• Understand the strengths and limitations of your
  approach
• Be able to justify your choice of study designs

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Resources to learn more

• Consultations re study design, conduct, analysis
  
• Ask for help before you start collecting data!!
• Email Dr Jim teWaterNaude (to ID appropriate
  support within School of Public Health)
• Self-learning
• Hulley SB, Cummings SR. Designing Clinical
  Research
• Gordis L. Epidemiology
• Szklo M, Nieto J. Epidemiology Beyond the Basics
• Friedman LM, Fundamentals of Clinical Trials

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IV. Examples
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1

• An investigator is interested in studying the
  association between schizophrenia and measles
  vaccinations.
• Hypothesis childhood vaccinations predispose
  individuals to develop schizophrenia in later
  life
• What study designs are possible?
• Which design would you recommend and why?

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2

• A study among outpatients attending the GSH
  diabetes clinic during 2004 collects data on 1432
  patients.
• Each patient is included once only in the dataset
  (ie, info from their first visit during 2004)
• Data are collected on patient family history,
  past treatment, knowledge of disease its
  management, disease severity (GTT)
• Medicine Registrar decides to examine whether
  patients with more severe disease have better
  knowledge of disease management
• What kind of study of this? What measures can be
  calculated?

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3

• You have collected records from your weekly
  clinic with information on 152 patients you have
  data on
• patient demographic characteristics
• detailed clinical information on morbidity
• medical history
• risk behaviours (smoking, drinking)
• medications
• You need to write an MMed. Quickly.
• Identify a research question, a study design, and
  describe these briefly.
• What are the strengths limitations of the study
  design you have selected in answering your
  specific question?

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4

• A study of neural tube defects and antenatal
  folate supplementation, lasting 10 years, follows
  10,000 pregnancies in which women used folate
  supplements, and 10,000 pregnancies in which no
  supplements were used.
• Among women taking folate supplements, 50 cases
  of neural tube defects were observed
• Among women not taking supplements, 150 cases of
  neural tube defects were observed.

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4

• What type of study is this?
• What is the appropriate measure of association?
• Draw up a 2x2 table, calculate the measure and
  interpret in one sentence

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5

• Another study of folate supplementation and
  neural tube defects uses a hospital referral
  system to identify all cases of neural tube
  defects in the local population.
• 200 cases are identified over 10 years (50 among
  women using supplements, 150 among women not
  using supplements).
• For comparison, investigators select 800 control
  pregnancies (where no neural tube defects were
  observed) at random from the same population (of
  whom 498 use folate supplements and 492 are
  unexposed).

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5

• What type of study is this?
• What is the appropriate measure of association?
• Draw up a 2x2 table, calculate the measure and
  interpret in one sentence.
• Comparing 4 and 5, what is the principle
  advantage of the case-control design to cohort
  design?