study design–person –place –time •characterized determinants –host –agent –environment...

Kami Memimpin We Lead


Intensive Course on Basic Statistics and Research MethodologyFor MMed (Year 2), MSc and PhD Candidates

Date: July 22 – 24, 2019 Venue: DK4 & DK7

Study Design


Methodology

• Study design• Reference/target

population• Source population• Sampling frame• Inclusion & exclusion

criteria• Sample size

determination• Sampling techniques

• Randomization techniques

• Study time and duration

• Tools and materials• Data collection• Intended statistical test• Operational definition• Ethical consideration• Framework of study


Epidemiologic study design

Epidemiologic studies

Descriptive

Aggregate

Ecological studies

Individual

Case report

Case series

Incidence

Cross sectional

Analytic

Experimental

Clinical trial

Community trial

Observational

Cohort

Prospective

Retrospective

Case-control Other


Epidemiologic study design


Descriptive

Aggregate

Ecological studies

Individual

Case report

Case series

Incidence

Analytic

Experimental

Clinical trial

Community trial

Observational

Cohort

Prospective

Retrospective

Case-control OtherCross

sectional


• Most common study design;

– Observational study

• Cross sectional study

• Case control study

• Cohort study

– Experimental study

• Randomized clinical trial


Descriptive vs analytic studies

• Descriptive

– Generate hypotheses

– Answer what, who, where and when

• Analytic studies

– Test hypotheses

– Answer why and how


Descriptive studies

• Characterised distribution;– Person

– Place

– Time

• Characterized determinants– Host

– Agent

– Environment

– Vector


Level of Evidence


Case Report and Case Series


Case report and case series

• Example;– Pure Primary Extragonadal Yolk Sac Tumor involving

stomach in a Young Child: A Case Report

– Gluteal Compartment Syndrome Following Alcohol Intoxication: Case Report and Literature Review

– Atypical Cellular Blue Nevus of the Foot: A Case Report

– Severe meningococcal serogroup W sepsis presenting as myocarditis: A case report and review of literature

– Incidental neuro-endocrine tumor of the appendix: Case report and literature review



• Case report

– Individual-level observations

– Describe particular phenomenon in a single patients

• Case series

– Describe more than one patients with similar problems


Case report and case series• A case report is a detailed report of the symptoms,

signs, diagnosis, treatment, and follow-up of an individual patient.

• Case reports usually describe an unusual or novel occurrence and as such, remain one of the cornerstones of medical progress and provide many new ideas in medicine.

• Some reports contain an extensive review of the relevant literature on the topic.

• The case report is a rapid short communication between busy clinicians who may not have time or resources to conduct large scale research.



• Reason for publishing a case report1. An unexpected association between diseases or

symptoms;

2. An unexpected event in the course observing or treating a patient;

3. Findings that shed new light on the possible pathogenesis of a disease or an adverse effect;

4. Unique or rare features of a disease;

5. Unique therapeutic approaches; variation of anatomical structures.



• Most journals publish case reports that deal with one or more of the following:– Unusual observations

– Adverse response to therapies

– Unusual combination of conditions leading to confusion

– Illustration of a new theory

– Question regarding a current theory

– Personal impact.



• Main objective to provide a comprehensive and detailed description of the case(s) under observation.

• This allows other physicians to identify and potentially report similar cases from their practice, especially when they share geographic or specific clinical characteristics.



• Case reports and case series are key hypothesis generating tools

• The lack of a comparison group is a major disadvantage.

• External validity (generalizability) is limited, given the biased selection of cases.

• Any association observed in a case report or acase series is prone to potentially unmeasured confounding unbeknown to the investigators.


Case report and case seriesAdvantages Disadvantages

One case to initiate a signal (case report)

No control

Provide stronger evidence wit multiple cases (case series)

Difficult to compare different cases

Observational Cases may not be generalizable

Educational Selection bias

Easy to do (fast and no financial support needed)

Unknown future outcome/follow-up

Identify rare manifestations of disease or drugs



• Guidelines To Writing A Clinical Case Report

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5686928/


Ecological Studies


Ecological studies

• Example;– Abortion laws reform may reduce maternal mortality: an

ecological study in 162 countries

– Social determinants of cancer incidence and mortality around the world: an ecological study

– Seasonal variation in the internet searches for gout: an ecological study

– Happier countries, longer lives: an ecological study on the relationship between subjective sense of well-being and life expectancy

– Country Characteristics and Variation in Diabetes Prevalence among Asian Countries–an Ecological Study


Ecological studies

• The first approach in determining whether an association exists may be a study of group characteristics, the so-called ecologic studies.

• In ecological studies the unit of observation is the population or community.

• Disease rates and exposures are measured in each of a series of populations and their relation is examined.

• Often the information about disease and exposure is abstracted from published statistics and therefore does not require expensive or time consuming data collection.


Ecological studies

• The populations compared may be defined in various ways.

– Geographical comparisons

– Time trends

– Migrants

– Occupation and social class


Cross-sectional Studies


Cross-sectional Studies

• A common study design used in initially investigating the association between a specific exposure and a disease of interest


Cross sectional studies

Exposure +

Exposure -

Outcome +

Outcome -



POPULATION

SAMPLES

IDENTIFY EXPOSURE, OUTCOME or CHARACTERISTICS simultaneously



• Variables– All measured at a single point in time, – No structural distinction between predictors and outcomes

• Aim: – To learn about the characteristics of a population at one point in

time.

• Results: – Estimates of the proportion/prevalence of population

characteristics.

• Types of cross-sectional study;– Descriptive– Analytical


Cross sectional studies• Example;

– Prevalence of health condition, prevalence of risk behaviour & risk factor

– Characteristics of knowledge, attitude, practice

– Monitor trend over time with serial cross sectional studies


CROSS-SECTIONAL STUDIES

• Descriptive cross-sectional study– Purely descriptive– Used to assess the frequency and distribution of a

particular disease in a defined population– The main outcome measure is prevalence

– Example: a random sample of school children in Kelantan to estimate the prevalence of asthma among 7-12 year olds.



• Descriptive cross-sectional study

School children in Kelantan

Samples

Asthma No asthma

N=25,000

n=2,633

n=174 n=2,459

Prevalence = 6.6%



• Descriptive cross-sectional study

– Alternatively, mean or median levels of population characteristics can be estimated (e.g.: mean systolic blood pressure, mean heart rate, etc)



• Analytical cross-sectional study– Used to investigate the association between a possible

risk factor and a health outcome

– Its yields weaker evidence for causality than cohort study

– Limited ability to draw a valid conclusions about any association or possible causality because the presence of risk factors and outcomes are measured simultaneously

– Risk of recall bias since collection of information about the risk factors is also retrospective



• Analytical cross-sectional study

School children in Kelantan

Samples

Asthma No asthma

N=25,000

n=2,633

n=174 n=2,459

Prevalence = 6.6%

Parent smoking

Parent not smoking

Parent smoking

Parent not smoking



• Analytical cross-sectional study

100

450

74

2009

0

500

1000

1500

2000

2500

Asthma No Asthma

Nu

mb

er o

f p

arti

cip

ants

Exposure Based on Group

Parent smoking Parent not smoking

Chi2 (1) = 150P<0.001


Cross sectional studies• When to use a cross sectional study?

– When objective is to determine prevalence / proportion

– When temporality of risk (exposure outcome) is not the aim of the study

– When both, the outcome and the exposure are relatively common.



• Advantages

– May study several outcomes, and several exposures

– Relatively short duration

– A good first step for a cohort study

– Yields prevalence and relative prevalence

• Disadvantages:

– Does not establish sequence of events (temporality)

– Not feasible for rare predictors or rare outcomes

– Does not yield incidence or true relative risk


Cohort studies


Cohort studies

• Cohort: a well defined group of individuals who share a common characteristics or experience.

• Example: individuals born in the same year.

• Also known as longitudinal study or follow up study.

• Participants classified according to exposure, followed up over time to ascertain outcome.

• E.g. nuclear power plant radiation exposure cancer events.


Cohort studies

• 2 types:

– Prospective cohort

– Retrospective cohort


Cohort studies


1. Prospective Cohort Studies

Present Future


2. Retrospective Cohort Study

Past Present


Cohort study• Advantage :

– Establish sequence of events (exposure outcome)– Can study several outcomes– Number of outcomes events grows over time– Yields incidence, relative risk and excess risk (true risk)– More control over selection of subjects– More control over measurements– Avoid bias in measuring predictors

• Disadvantage :– Requires more time, money and human resources.– Larger sample size– More expensive– Longer duration


Case-control studies


Case control studies

• When to conduct;

– To study rare disease/ outcome

– To study multiple exposures that may be related to a single outcome

– Funding or time is limited



• Subjects

– Case and control have the same population of origin

– Always start with cases, the find appropriate control

• Case:

• Have outcome of interest

• Representative sample of all cases in the general population

• Control:

• Do not have outcome of interest

• Representative sample of the general population



• Advantages

– Use for studying rare conditions (outcomes)

– Less expensive

– Relatively smaller sample size

– Shorter duration than prospective study

– Able to study multiple risk factors/exposure for 1 disease

– Yields odds ratio (estimation of true risk)



• Disadvantages

– Exposure obtained after diagnosis (disease exposure)

– Does not establish sequence of events

– Potential for bias and confounding from sampling two populations

– Dependent on the subject’s memory

– Difficult to identify appropriate control group

– Limited to one outcome variable

– Does not yield prevalence, incidence or excess risk


Experimental Study Design

Clinical Trials


Clinical Trials

• A test of a new intervention or treatment on people

• Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions (e.g., drugs, diagnostics, devices, therapy protocols).


Clinical Trials

• A randomized controlled trial (RCT) is a specific type of scientific experiment, and the gold standard for a clinical trial.

• New treatment given to a group of patients (treated group) and another treatment given to another group of patients (control group) at the same time – concurrently controlled

• Patients allocated to groups by randomization


Types of Clinical Trials

• Treatment/Drug trials

• Prevention trials

• Screening trials/Diagnostic trials

• Quality-of-life studies/supportive care studies

• Genetic trials

• Etc


Key Features in Clinical Trials

• Intervention (experimental) studies in clinical setting Clinical trials

• Similar to cohort study, except that “exposure” are allocated rather than observed.


Experimental vs observational studies

Experimental studies Observational Studies

Examples Randomized Clinical TrialsQuasi-experimental trialsCluster Randomized trials

CohortCase-controlCross-sectionalCase-series

Group assignment is based on

Researcher assigns groups “Natural Conditions” (personal preference, genetics, social determinants, environment, etc)

Use “Gold Standard” for studying therapeutic interventions (treatments) or prophylactic interventions (prevention)

Association between health outcomes and exposures. This can include studies on diagnosis, prognosis, aetiology or harm


Advantages and Disadvantages• Advantages

– Gold standard for evaluating efficacy of therapeutic or preventive measures.

– Provides strongest evidence for causality.– Reduces influence of other determinants of exposure and

outcome (confounding) due to randomization.

• Disadvantages– Expensive, time-consuming.– Subjects may not be representative of all people who might

eventually be put on the treatment.– Ethical considerations (equipoise necessary) – believe new

treatment is at least as good as old treatment or placebo.


Structure of a Clinical Trial

• Recall cohort study

Exposed

Non-Exposed

Event

No Event

Event

No Event

Exposure not manipulated by researcher


Structure of a Clinical Trial

• Clinical trial

Exposed

Non-Exposed

Event

No Event

Event

No Event

Exposure manipulated by researcher


Structure of Clinical Trials

• All elements are the same as for a cohort study except that treatment is assigned by researcher (either by randomization or not) rather than by physician and patient choice.

• The “exposures” are treatments, and the “outcomes” are any possible end result of treatment

• The patients to be studied are first selected from a larger number of patients with the condition of interest.


Structure of Clinical Trials• Patients are then divided into two (or more) groups of

comparable prognosis. • One group, called the experimental group, is exposed to an

intervention that is believed to be better than current alternatives.

• The other group, called a control (or comparison) group, is treated the same in all ways except that its members are not exposed to the experimental intervention.

• Patients in the control group may receive a placebo, usual care, or the current best available treatment.

• The course of disease is then recorded in both groups, and differences in outcome are attributed to the intervention.


Structure of Clinical Trials

• The main reason for structuring clinical trials in this way is to avoid confounding when comparing the respective effects of two or more kinds of treatments.

• The validity of clinical trials depends on how well they have created equal distribution of all determinants of prognosis, other than the one being tested, in treated and control patients.


Elements of Clinical Trials• Ethics

– more ethical issues compared to observational studies

• Sampling – non-random / volunteer

• Intervention – allocated by researcher (in randomized trial)

• Comparison groups – may or may not have comparison group

• Allocating treatment – randomization

• Blinding – none / single / double / triple

• Assessment of outcomes – primary outcome/ secondary outcome / surrogate outcome / composite

outcome / adverse effects


Recap


Descriptive

Aggregate

Ecological studies

Individual

Case report

Case series

Incidence

Analytic

Experimental

Clinical trial

Community trial

Observational

Cohort

Prospective

Retrospective

Case-control OtherCross

sectional


References• Sayre, J. W., Toklu, H. Z., Ye, F., Mazza, J., & Yale, S. (2017). Case reports,

case series–from clinical practice to evidence-based medicine in graduate medical education. Cureus, 9(8).

• Guidelines To Writing A Clinical Case Report. (2017). Heart views : the official journal of the Gulf Heart Association, 18(3), 104–105. doi:10.4103/1995-705X.217857

• https://www.bmj.com/about-bmj/resources-readers/publications/epidemiology-uninitiated/6-ecological-studies

• David D Celentano, S. M., & Szklo, J. H. S. P. H. M. (2018). GordisEpidemiology: Elsevier Health Sciences.

study design–person –place –time •characterized determinants –host –agent –environment...

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