Study types

Module 3

Study Types/Designs

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Module 3- Study types/designs

Learning ObjectivesAt the end of this section, you will be able to: Describe the common types of study designs

used in HSR. Mention the advantages and limitations of each

type of study design Identify the most appropriate study design for the

research proposal you are developing.

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Study types or study designs

The type of study chosen depends on: The type of problem; The knowledge already available about the

problem; and The resources available for the study.

Study designs broadly can be classified as interventional or non interventional studies.

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Study design….

Table: Classification of research study designs

I. Non-interventional (observational) studies Exploratory Qualitative Ecological (correlational) population as

study unit Descriptiv

e Studi

es

Epidemiologic

al stud

y designs (Quantitative)

Case reports Case series Cross-sectional surveys

individual as

study unit

Cross-sectional comparative study

Case control

Cohort

Analytical

Studies

II. Interventional studies Experimental studies (Randomized)

Quasi-experimental studies (Not Randomized)

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Study designs…An EXPLORATORY STUDY is

a small-scale study of relatively short duration, carried out when little is known about a situation or a

problem. It may include description as well as comparison.

It may include description as well as comparison.

For example: Description: To explore needs of HIV positive and AIDS

patients, a number of in-depth interviews can be held with various categories of patients (males, females, married, single) and with some counselors working on a program that is already under way.

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Exploratory study… Comparison: To identify variables that help

to explain why one group of persons or objects differs from another.

To explain the differences we observe (e.g., in the needs of male and female AIDS patients) or to identify causes of problems.

Note: If the problem and its contributing factors are not well defined, it is always advisable to do an exploratory study before embarking on a large-scale descriptive or comparative study.

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Study designs….

EPIDEMIOLOGICAL STUDIES: Purpose

Descriptive studies Analytic studies

Characterize disease occurrence by time, place and person.

Generate testable hypothesis as to the cause of disease

Concerned with thesearch for causes and effects.

Test hypothesis aboutassociation betweenexposure and outcome.

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Study designs…

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Study designs…10

Descriptive studiesA. Dealing with individuals- Case report/case study- Case series- Cross sectional surveys (usually)B. Dealing with population- Correlational or ecological(some times)

Case Report/case study11

Careful and detailed report of the profile of a single patient by one or more clinicians

• Document unusual medical occurrences

• Can generate hypothesis, provide clues in identification of a new disease or adverse effects of exposures (E.g. It was a single case report that formulated the

hypothesis of oral contraceptive use increases venous thromboembolism)

It is made using Simple history, physical examination and Lab./ radiologic

investigation

Case Series Studies

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Description of clinical/epidemiologic characteristics of a number of patients (usually 5-12) with a given disease having similar diagnosis

• Collection of individual case reports occurring within a fairly short period of time

Used as an early means to identify the beginning or presence of an epidemic, generate hypothesis and gives information about natural history of disease

Can suggest the emergence of a new disease (i.e. PCP …. AIDS)

Example of case-series studies Five young, previously healthy homosexual

men were diagnosed as having PCP at Los Angeles hospital during a six month period from 1980 to 1981

This form of pneumonia had been seen almost exclusively among older men and women whose immune systems were suppressed

This unusual circumstance suggested that these individuals were actually suffering with a previously unknown disease, subsequently it was called AIDS

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Uses of case series studies

Can be valuable early evidence for associations between exposures and diseases which can be studied in more detail

Useful for the recognition of new diseases, Useful for constructing of the natural

history of a disease, Use to formulate a hypothesis and to

detect an epidemic

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Cont….15

Limitations of case report and series studies :

• No appropriate comparison group • Based on the experience of one person so Can’t be used to test for presence of a valid

statistical association …prone to atomistic fallacy not a true epidemiologic design

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Cross-sectional study Measure disease and exposure status

simultaneously among individuals in a well-defined population at a point in time …..also called a “prevalence study/survey”)

Snapshot of the health status of populations at a certain point in time

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Cont… Can have descriptive or analytic purposes The descriptive type is carried out to study prevalence

of health related events at a point in time/snapshot Diseases, risk factors, coverage of interventions, health

service utilization, knowledge, attitude and practice The analytic type is carried out to assess association

between exposure and outcome Exposure and disease status are assessed

simultaneously among individuals at the same point in time

Compare prevalence of disease in persons with and without the exposure of interest

Measures of association is made using odds ratio

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Cross-Sectional Studies….

Steps in the conduct of cross-sectional studies:

1. Define a population of interest (reference or source population)

2. Recruiting a representative sample (adequate size, random selection)

3. Measure the variables of interest (disease &or exposure) at the same point in time

4. Analyze the data

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Example: Respiratory problems

Yes no total Smoking Yes 70 50 120 no 30 70 100

Total 100 120 220Prevalence of smokers (among respiratory problems) =70 x100=70% 100

Prevalence of respiratory problems (among smokers) =70 x100=58.3%

120

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Examples…

General household surveys National Health and Nutrition Examination

Survey International surveys (International Study

of Asthma and Allergies in Childhood (ISAAC)

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Cross-sectional Study…. Advantage: helps to determine prevalence …disease

burden Fast/Inexpensive - no waiting! No loss to follow up multiple factors and outcomes at same point

in time can be studied Helps to generate hypotheses

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Cross-sectional study….Disadvantage Cannot determine causality

Temporal sequence between exposure and disease can’t be established, i.e. which came first, chicken or the egg?

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Ecologic Studies A study in which one or more exposures or

disease is measured at the population level rather than the individual level

Uses data from entire population to compare disease frequencies (average values) - between different groups during the same

period of time, or - in the same population at different points in

time. Correlation coefficient (r) is the measure of

association

Examples of correlational studies

1. Trend of HIV in Ethiopia HIV prevalence of Ethiopia at different years or

points in time2. Geographic distribution of HIV in the regions of

Ethiopia HIV prevalence of different regions of Ethiopia

at the same year or point in time3. Fluoride content of water and dental caries

(correlation) Proportion of people with dental caries in

villagesVs

Fluoride content of water in villages during the same period or point in time

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Breast Cancer Mortality and Dietary Fat Intake

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Ecologic correlation of breast cancer mortality and dietary fat intake

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Ecologic Studies…Limitation Lack of ability to control for effects of

potential confounding factors. Inability to link exposure with disease at

individual level association found with aggregate data

(average values) may not apply to individuals (Prone to ecological fallacy)

Measurement limitation (Ecological conditions are difficult to measure at individual level) E.g environmental contact, fluoride content of

water

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Ecological fallacy: example

Imagine a study of the rate of coronary heart disease in the capital cities of the world relating the rate to average income.

Within the cities studied, coronary heart disease is higher in the richer cities than in the poorer ones.

We might predict from such a finding that being rich increases your risk of heart disease, but

In the industrialised world the opposite is the case - within cities such as London, Washington and Stockholm, poor people have higher CHD rates than rich ones.

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Atomistic fallacy

Studies of individuals, case report and case series study, are prone to the opposite of the ecological fallacy, the so-called atomistic fallacy.

Wrongly assuming from observations on the causes of disease in individuals that the same forces apply to whole populations.

For example, at an individual level a high income or a marker of material success such as employment, car access etc., is associated with a lower rate of suicide. But,

Does not mean that populations or societies which are rich have a lower rate of suicide or better mental health, rather the opposite seems to be true.

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Study designs…Assignment

of exposure by researcher

yes no

Random allocation to comparison gps

yes No

Experiment e.gRandomizedClinical trial

Quasi- experiment

yesno

Comparison

Descriptive Case-control cohort

Observational Interventional

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ANALYTIC STUDIES Focuses on identifying determinants of a disease by testing the

hypothesis formulated from descriptive studies the ultimate goal is judging whether a particular exposure

causes or prevents disease (unwanted health related event) Analytic studies are broadly classified into two -

observational and interventional studies. Both types use "control group", the use of control group

(comparison grp) is the main distinguishing feature of analytic studies.

In Observational, information is obtained by observation of events.

No intervention is done, no deliberate interference with natural course of disease. (cross-sectional, case control, cohort)

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Cont…In Interventional study, the researcher does

something about the exposure and observes the changes on the outcome or disease.

Investigator has control over who gets exposure and who don't.

The key is that the investigator assign study participants into either group, whether it is done randomly(RCT, Experimental) or not randomly (quasi-experimental).

Always prospective

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Cohort Studies Cohort

a group of people who share a common experience or condition

E.g. Birth cohorts, cohort of smokers, occupational exposures Cohort studies

The observation of a cohort over time to measure outcome(s) Because the data on exposure and disease refer to different

points in time, cohort studies are longitudinal Longitudinal, follow-up or incidence studies

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Cont… They have 2 primary purposes:

Descriptive: to describe the incidence rates of an outcome

Analytic: to analyze associations between the outcomes and risk factors (Usual type)

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Cont… begin with a group of people free of disease who are classified into subgroups according

to exposure to a potential cause of outcome and the whole cohort is followed up to see how

the subsequent development of outcome differs between the groups with and without exposure (Figure below)

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Figure 1- design of cohort study

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Types of Cohort Studies Closed vs. Open

Closed cohort: exposure groups are defined at the start of follow-up and no new members are added during the follow-up

Open/dynamic cohort: people move in and out the study

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Cont…

Incidence cohort vs. Prognostic (clinical) Incidence Cohort Study

To assess incidence of disease To identify risk factors for disease onsetIncidence greater in exposed than non-

exposed?

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Cont…

Prognostic Cohort StudyFollow diseased cohort to assess factors

associated with outcome (recovery or death)

Goal is to identify explanatory/prognostic factors/ factors helped to the dev’t of the out come of the disease.

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Cont… Prospective vs. Retrospective (Concurrent vs.

Non-concurrent) Depending on temporal relationship between

initiation of the study and time of collection of exposure and outcome data from the study subjects or participants

Cohort studies have been called prospective studies, but this terminology is confusing and should be avoided the term “prospective” refers to the timing of data collection

and not to the relationship between exposure and effect Thus, there can be both prospective and retrospective

cohort studies

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Prospective cohort studies Exposure and outcome data is

collected after start of the study cohorts Identified in the present exposure status or possible

explanatory/prognostic factors determined in the present

Cohorts followed-up to identify outcome Ascertainment of outcome done in future

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2016 2017 2018

Fig. 2. Design of prospective cohort studies

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Cont… Advantages

Exposure precedes outcome Outcome unknown when exposure determined Can examine many outcomes of the exposure

Disadvantages Cost Time delays Loss to followup

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Retrospective cohort studies all the exposure and effect data have been

collected before the actual study begins This type of investigation is called a historical

cohort study Conduct

Identify cohort in the past using records/databases

Determine exposure or prognostic factors in the past using again records or databases then

Identify outcome in past or present or future (in case of mixed cohort)

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Cont… Costs can occasionally be reduced by using a historical

cohort (identified on the basis of records of previous exposure)

This sort of design is relatively common for studies of cancer related to occupational exposures

For example, records of military personnel exposure to radioactive fall-out at nuclear bomb testing sites have been used to examine the possible causal role of fall-out in the development of cancer over the past 30 years

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2013 2014 2015

Fig. 3. Design of retrospective cohort studies

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Cont… Advantages:

Do not require a very long time (exposures and/or outcomes have already occurred)

Cheap, if used record linked for outcomes Disadvantages:

Feasible only when a list of exposed individuals is available Exposure data often of poor quality Usually unable to measure confounders

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Design and data collection of cohort study (1)

1. Define and identify cohorts 1.1. Identify population at risk Selection of Exposed Population

Depends on research question Depends on frequency of exposure

Common exposures: general populationRare exposures: selected groups

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Design and data collection (2)

Outcome must not be rare in exposed Attributable risk must be high Accessible and compliant subjects

E.g., Nurse’s Health Study, Physicians Selection of Non-exposed Group

Similar to exposed Control for confounding factors

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Design and data collection (3)1.2. Screen identified subjects for the disease

and omit the prevalent cases2. Define, assess, identify and classify

exposure3. Follow-up and ascertain outcome

Timing of outcome events-case definition

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SamplingSample size - for test of significant difference

between two proportions, the following formula can be used:

Parameters:n - size of sample in each groupP1 ,P2–estimated population prevalence in the

comparison groupsβ = 1- Power (the probability that if the two

proportions differ the test will produce a significant difference) Usually a power of 80% is used

2

21

22112

2 11pp

ppppZZn

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Analysis (statistically prospective cohorts are summarized using RR but retrospective by OR)

RR=incidence exp/inc non exp Presence of association

Population RR=1 – no association; RR<1 – negative

association; RR>1 – positive association Sample

P-value<0.05 – statistically significant association

RR≠1 Statistical methods – survival analysis

Strength of association Weak – RR close to 1; Strong – RR far from

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Case control study

Design concept Starts with cases and comparative group(control)

We determine what proportion of cases were exposed and what proportion were not

We also determine what proportion of controls were exposed and what proportion were not

Also called case-referent or retrospective

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Case-control….cont

Study popcases

controls

exposed

Not exposed

Not exposed

exposed

Study begins here

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Designing case control studies

I. Selection of cases (definition, eligibility criteria) Hospitals, other medical care facilities/general population

II. Selection of controls (definition, eligibility criteria) General population, neighborhood, friends/relatives,

hospital or clinic-based ***The benefit of increased sample size is not as

relevant past the 1:4 ratio (e.g. increase in statistical power).

III. Ascertaining Exposure Sources of exposure data (cases and controls)

***The measure of association in case control study is Odds Ratio(OR)

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Advantages of Case-Control Studies Quick and easy to complete, cost

effective Most efficient design for rare

diseases Usually requires a smaller study

population than a cohort study

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Uncertainty of exposure-disease time relationship

Inability to provide a direct estimate of risk

Not efficient for studying rare exposures Subject to biases (recall & selection

bias)

Disadvantages of Case-Control Studies57

INTERVENTION STUDIES58

Investigator determines who is exposed, ideally using random methods

Investigator allocates the exposure and follows for an outcome

Types of interventional studies include Randomized Clinical Trials Field Trials Community Intervention Trials Quasi-experimental Studies

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What is an experimental study?

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Randomized controlled trials are sub-types of cohort studies in which exposure (i.e., treatment) is randomly assigned by the investigator (or by some other, observable phenomenon)

Have a long history in clinical medicine Although experimental studies come in

many types, principles are the same and clinical trials dominate the field

What is a clinical trial?61

A clinical trial is a prospective study evaluating the effect and value of intervention(s) in human beings under pre-specified conditions.

A controlled clinical trial is a prospective study comparing the effect and value of intervention(s) against a control in human beings.

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The clinical trial is the most definitive tool for evaluation of the applicability of clinical research.

It represents a key research activity with the potential to improve the quality of health care and control costs through careful comparison of alternative treatments.

When might a RCT be indicated?

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Exposure is a modifiable factor which persons will let you modify, e.g., taking a pill, trying a different diet

When there is ethical equipoise, that is when we really do not know whether a particular exposure is associated with benefit or with harm- Imperative that informed consent be obtained

A particular exposure may have an influence on multiple outcomes of tremendous importance

In experimental trials, in contrast with other epidemiologic study designs we have discussed, we are doing something to participants so we have to be certain that, first, we do no harm

Clinical Trial Phases64

Phase I: clinical pharmacology and toxicity

Phase II: Initial Assessment of Efficacy Phase III: Full-scale Evaluation of

Treatment Efficacy Phase IV: Postmarketing Surveillance

Phases…

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Phase I: clinical pharmacology and toxicity

1st experiment in human for new drug, schedule, or combination

Primary concern: Safety Goal: define the maximum tolerated dose

(MTD) in a dose-escalation study Typically required 15-30 patients

Phases…66

Phase II Small randomized, controlled, blinded Tests tolerability and different doses

E.g., optimal dosage without side effects Applied to patients with relevant illness Goal - Identify suitable formulation of drug

Intervention Trials67

Phase III Referred to as clinical trial Evaluation of efficacy of drug Usually randomized, blinded, controlled trial If successful, licensed and marketed

Phase IV Large studies after approval of drug Often observational, study long-term effects

Long term efficacy, rate of serious side effects Evaluate drug in “real life”, additional uses

Conducting Trials68

1. Selecting participants2. Measure baseline characteristics and

describe sample3. Randomizing4. Apply intervention5. Follow-up and adherence to protocol6. Measuring outcome7. Analysis

1. Selection of Participants69

Terminology Target population

People to which findings will be generalized

Study population Subset of target population available/accessible

to study

Selecting subjects Establish inclusion/exclusion criteria Sample size

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Source population

Study population

Randomize

Treatment No treatment

threats to external validity

threats to internal validity

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Population At Large

Population With Condition

Study Population

Study Sample

Define Condition

Entry Criteria

Enrollment

Sample size72

Calculating sample sizes for trials with dichotomous outcomes (eg, sick vs well) requires four components:

type I error (α), power, event rate in the treatment group(p1), RR or event rate in the control group(p2)

,RR=P1/p2

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Participants74

Inclusion criteria Define main characteristics of target population

that are relevant to research question Demographic characteristics

E.g., adults, aged 20-69 Clinical characteristics

E.g., in good health Geographic characteristics

E.g., living in northern Ethiopia Temporal characteristics

E.g., inception period Jan 1, 2003 to Dec 31, 2003

Participants75

Exclusion criteria Subsets of people meeting inclusion criteria (potentially

suitable for research question) except for characteristics that might interfere with quality of data etc.

High likelihood of being lost to follow-up E.g., transients

Inability to provide good data E.g., language barrier or cognitive incapacity

High risk for side effects E.g., pregnant, lactating

Unethical to withhold treatment E.g., severe depression

Exclusion Criteria76

Five main reasons for exclusion from clinical trial Safety concerns (susceptibility to adverse

effects of active treatment) Unethical to withhold treatment (tx so

beneficial for some not acceptable to assign placebo

Active treatment unlikely to be effective Unlikely to adhere to treatment Unlikely to provide outcome information (e.g.,

die or move before study completion)

Conducting Trials77



2. Baseline Characteristics78

Need enough information to track subjects Contact persons; address, etc.

Description of participants Aid in assessing generalizability (e.g., gender,

age, disease severity, etc.) Risk factors for outcome or to define

subgroups E.g., smoking status, smoking status of spouse

Measure of “outcome” variable E.g., if pain is “outcome”, need baseline pain

Conducting Trials79



3. Randomization80

Should be done at the last possible moment, after eligibility criteria has been determined and informed consent has been obtained

Important to conceal randomization scheme from attending health care providers

Advantages of Randomization

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Removes the potential of bias in the allocation of participants.

Prevents confounding produce comparison groups

Methods of randomization82

Fixed allocation Randomization simple Randomization Stratified Randomization

Stratified Randomization83

Select factor(s) of interest Stratify (divide) group by that factor Randomize the appropriate proportion of

each group into your treatment groups Increases the likelihood that your

treatment groups will be comparable on that factor

Stratified Randomization84

E.g., age is important in treatment response 100 in sample want 50 per group Say 20% of sample are >60 (high risk

group) Randomly select 10 people over 60 for each

group Then randomly select 40 people under 60

for each group

Conducting Trials85



4. Applying Intervention86

Intervention strategy compared with Placebo Standard treatment

May have more than one comparison group Advantages, disadvantages of “placebo”?

Ethical issues Advantages, disadvantages of “standard

treatment” control? Interpretation of findings?

Blinding87

Randomization Control for confounding bias at baseline Does not control for confounding during follow-

up E.g., differential attention to subjects in treatment arm

Does not control for information bias Blinding

Controls for Information bias (e.g., observer bias) Reduce loss to follow up (reduce selection bias)

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Blind studies

Single blind The patients do not know which treatment they receive

Double blind The patient and the observer or the physician do not know

Triple blind The patient, the observer and the analyst do not know

Conducting Trials89



5. Follow-up and Adherence90

Ideally All subjects adhere to treatment regimens;

do not seek additional treatment; do not drop out, die, move or have to be withdrawn from study; attend follow-up sessions and provide outcome data

Unplanned Crossovers91

Unplanned crossover is said when subjects switch to either treatments

When subjects choose the alternative treatment Subjects in experimental group start using

“control” treatment or vice versa Usually have selective cross-over (more

subject from one group cross over) A large proportion of crossovers may

invalidate study

Conducting Trials92



6. Measuring Outcome93

Outcome should be Clinically relevant Feasible

E.g., choose outcome that is sufficiently common for time and number of subjects

Able to be measured accurately and precisely Not too costly

Above all, valid, reliable and sensitive to change

Conducting Trials94



Analysis95

Analyze according to which treatment the patient was randomized to (which treatment was intended?) “intention to treat” analysis

Or according to which treatment they actually received? “per protocol” analysis

Intention to treat vs. per protocol analysis96

Intention to treat analysis (management trial):

Includes all randomized patients in the groups to which they were randomly assigned, regardless of their adherence with the entry criteria, regardless of the treatment they actually received, and regardless of subsequent withdrawal from treatment or deviation from the protocol

ITT---cont97

Key points Use every subject who was randomized

according to randomized treatment assignment

Ignore noncompliance, protocol deviations, withdrawal, and anything that happens after randomization

As randomized, so analyzed

Intention to treat---cont98

AdvantageRandomization is preservedSimulate the real worldDisadvantage: If many patients switch treatment,

difference b/n groups will be obscured

Per protocol---cont99

Per protocol analysis: Patients who deviate from the protocol are

excluded from the analysis

Advantage: determine efficacy of intervention

Disadvantage: vulnerable to all source of bias

QUASIEXPERMENTAL STUDIES100

In these studies, one characteristic of true experiment (i.e randomization ) is missing.

But, they always include intervention or manipulation of the independent variable.

The common quasi-experimental studies are described below. a)Non-equivalent control group design b) Before-After Study design

Non-equivalent control group design101

Uses two or more groups (one serves as a control group)

The subjects in study (intervention) group and control group are not randomly assigned.

Figure: Diagram of a quasi-experimental design with two groups

Before-After Study design 102

Uses only one group in which an intervention is carried out. The situation is analyzed before and after the intervention to test if there is any difference in the observed problem.

Figure: Diagram of a before-after study

Quasi-experimental studies…103

Advantage of quasi-experimental designs: Often more practical than randomized

studies.

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Study types….

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Study types

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