case control & cohort study
TRANSCRIPT
CASE CONTROL
AND COHORT STUDY
Dr. Bhumika Bhatt
Junior Resident
CONTENTS:
DEFINITION TYPES OF STUDY ANALYTICAL STUDIES CASE CONTROL STUDY VARIANTS OF CASE CONTROL STUDY SUMMARY COHORT STUDY DIFFERENCE SUMMARY REFERENCE
EPIDEMIOLOGY The most conventional definition of epidemiology
is "the study of the distribution and determinants of health-related states or events in specified populations, and the application of this study to control health problems." ( John M.Last,1988)
TYPES OF STUDY
Experimental Observational
RCT Non RCT
Analytical Descriptive
Ecological Cross-sectional Case-control Cohort
ANALYTICAL STUDIES In analytical studies , the subject of interest is the
individual within the population. The object is not to formulate but to test the
hypothesis. To evaluate an association between exposure and
disease. Analytical studies focuses on the magnitude of the
association between the exposure and the health problem under the study.
CASE-CONTROL STUDY (RETROSPECTIVE STUDY) Unit of Study: Cases/Control(Individuals) Study Question : What had happened Direction of Inquiry: E O Study Design:
CasesNot
Exposed
Exposed
Control
Expose
d
Not Exposed
CASE CONTROL STUDY A case–control study is an observational study in
which subjects are sampled based upon presence or absence of disease and then their prior exposure status is determined.
Distinct feature:
a. Both exposure and outcome (disease) have occurred before the start of the study.
b. The study proceeds backwards from effect to cause.
c. It uses a control or comparison group to support or refute an inference.
BASIC DESIGN
RISK FACTORS
CASES(Disease Present)
CONTORLS(Disease Absent)
PRESENTa b
ABSENT c d
Total a+c b+d
BASIC STEPS Selection of cases and controls. Matching. Measurement of exposure and Analysis and interpretation.
CASES SELECTION
Study begins with cases, i.e. the patients in whom the
disease has already occurred.
Patients with the disease in question (cases) were
enquired for all the details of their exposure to the
suspected cause.
The new cases, which are similar clinically,
histologically, pathologically and in their duration of
exposure (stage) will be chosen to avoid any error and
for better comparison.
CASES SELECTIONDefinition of case: it involve two specifications-
(i) Diagnostic criteria :Enunciate clear cut diagnostic criteria for the disease of interest. As far as possible use criteria given by expert bodies.
(ii) Eligibility criteria : It is always advisable to take the incident cases since the prevalent cases might have changed their exposure status due to medical advice etc.
Sources of Cases Hospitals. General population:
SELECTION OF CONTOLS Controls must be free from the disease under
study. The usual principle that is to be observed while selecting controls should be that “like should be compared with the like” to avoid errors and for better comparison .
Sources of controls: Hospital controls General population Relatives/Neighborhood
To Do To Avoid
Select controls from various diagnostic groups so no particular risk factors will be overrepresented
Do not select patients who have multiple concurrent conditions
Select controls from patients with acute conditions so earlier exposures could not have been influenced by the condition
Do not select patients with diagnoses known to be related to the risk factor of interest
-Source of controls (healthy population based or hospital based)- No. of controls- No. of control groups- Method of sampling the controls- Matching, if considered.
STRENGTHS OF POPULATION-BASED AND HOSPITAL-BASED CASE-CONTROL STUDIES
Population-Based Hospital-Based
Source population is better defined Subjects are more accessible
Easier to make certain that cases and controls derive from the same source population
Subjects tend to be more cooperative
Exposure histories of controls more likely to reflect those of persons without the disease of interest
Easier to collect exposure information from medical records and biological specimens
CONFOUNDING FACTOR Defined as one which is associated both with
exposure and disease and is distributed unequally in study and control groups.
Confounder
Exposure outcome
(i)Associated with the exposure of interest.(ii) Related to the outcome of the interest.(iii) It should not be in the direct chain or link between the exposure and outcome
Hypothesis:Whether consumption of alcohol is a risk factor for oral CA.
100 cases of oral CA and 100 healthy subjects were asked regardingthe history of alcohol consumption during past 15 years.
Odds ratio= (a x d / b x c)= (80 x 80) (20 x 20) = 16
Risk of getting oral cancer is 16 times higher if a person drinks alcohol.
History of Alcohol
Oral CancerPresent
Oral Cancer Absent
Total
Present 80 20 100
Absent 20 80 100
Total 100 100 200
Due to the “hidden” effect of tobacco use becausepeople who drink alcohol are also often the ones who also use tobacco; and tobacco use is itself a direct cause of oral cancer, whether one drinks or not.
Findings may be false:
Dissecting hypothetical data into two strata
Tobacco Users
Non-Tobacco Users
Stratum OR=60x5/20x15 =1
Stratum OR= 5x 60/15 x 20=1
Conclusion :Both the strata OR falls to 1 i.e. there is no risk of cancer from alcohol after adjusting for the effect of tobacco
METHODS FOR CONTROLLING CONFOUNDING Randomisation: If a group of subjects is divided
into two , using “random allocation” (syn. Randomization) the 2 groups will be similar to each other in all respect.
Restriction: the subjects having the particular confounding variable(s) are not taken up at all.
Matching
MATCHING
Defined as the process by which we select controls in such a way that they are similar to cases with regards to certain pertinent selected variables (e g. age, sex, occupation, social status etc. ) which are known to influence the outcome of the disease.
MATCHING
Advantages Disadvantages
May increase the precision of case-control comparisons and thus allow a smaller study.
May be time-consuming and expensive to perform.
The sampling process is easy to understand and explain.
Some potential cases and controls may be excluded because matches cannot be made.
If analyzed correctly, provides reassurance that matched variables cannot explain case-control differences in the risk factor of interest.
The matched variables cannot be evaluated as risk factors in the study population.
MEASUREMENT OF THE EXPOSURE Information about the exposure should be obtained
in precisely the same manner for both cases and controls.
This may be obtained by the interviews, by questionnaires, or by studying past records of cases such as hospital records, employment records.
ANALYSISThe final step is Analysis:
Exposure rate among cases and controls to suspected factors.
Estimation of the Disease risk associated with exposure (Odds ratio).
CASE CONTROL STUDIES OF SMOKING AND LUNG CANCER
CASES (WITH LUNG CANCER
CONTROLS (WITHOUT LUNG CANCER)
SMOKERS 33(a) 55(b)
NON SMOKERS 2(c ) 27 (d)
TOTAL 35 (a + c) 82( b + d)
ANALYSIS: Exposure rates:
A. Cases a/a + c = 33/35 = 94.2%.
B. Controls = b/b + d = 55/82 = 67.0% This shows frequency rate of lung cancer is
definitely higher among smokers than among non-smokers.
The chance of something happening can be expressed as a risk and/or as an odds
Risk = the chances of something happening
the chances of all things happening
Odds = the chances of something happening the chances of it not happening
Example-1: If we choose a student randomly from your class of say 9, how likely is it that you will be chosen?
Risk (probability) = 1/9 = .111
Odds = 1/8 = .125
Example-2: Among 100 people at baseline, 20 develop influenza over a year.
The risk is 1 in 5 (i.e. 20 among 100) = .2
The odds is 1 to 4 (i.e. 20 compared to 80) = .25
ODDS RATIO
Measure of strength of association between risk factors and outcome.
Odds ratio= P/1-P, P= Probability The odds ratio is also known as the cross-products ratio Based on 3 assumption:
1. Disease being investigated must be relatively rare. In fact majority of the chronic disease have a low incidence in the general population.
2. The cases must be representative of those with the disease.
3. The controls must be representative of those without the disease.
ODDS RATIO
Cohort study Case control study
ODDS RATIO Odds Ratio : ad/ bc
33 X 27/55 X 2 = 8.1 Odds ratio is a Key Parameter in the analysis of case
control studies. It interprets that odds of cases being exposed are so
many times higher compared to the odds of controls being exposed.
In our example risk of lung cancer due to smoking is 8.1 as compared to non smoking.
BIAS IN CASE CONTROL STUDIES Selection Biases
Berksonian Bias : The probability of admission to hospital or detection of the outcome (disease) may be more among the cases simply because of the exposure.
Selection of inappropriate Cases or Controls : Cases or controls who do not have adequate chance of exposure.
Self selection Bias : Patients who are admitted to a particular hospital and hence taken as cases may be systematically very different from most of the patients with the disease but who are not admitted to that hospital, as regards the exposure status.
Survivorship Bias : Case control study generally takes the patients who are living. Cases who have died are generally not taken and these may be systematically very different from living case as regards the exposure status
Selection of wrong control group : Controls who are not from the same source population from where the cases have come; selection of close friends of cases - since they would in general have the same behavioural factors as cases (birds of a feather flock together ), example of condom use and STDs.
Information (measurement) Biases Recall bias : Cases who are suffering from a disease are likely to recall much more
as regards their exposure (example on congenital malformation and exposure to X - rays).
Observer bias : If observer is aware of the case - control status, he/she may subconsciously tend to ask much more from cases.
Confounding Bias
VARIANTS OF CASE CONTROL STUDIES
NESTED CASE CONTROL STUDY Combines the advantages of a cohort and a case
control study. Firstly , the study becomes inexpensive and take
care of the logistics. Secondly, we can calculate the incidence of the
disease which would not have been possible in a usual case control study.
Thirdly, the problem of recall bias and that the controls may be from a different source population than cases (which occur in case control study) have been prevented.
Watch for 15 - 20 years
20 randomly selected samples of
those whohave not developed
mental illness (controls)
analyse these 40 samples for serum
lithium andmake comparisons between the two
groups
20 cases of mental disease(cases)
Rest of the cohort is continously folowed
Rest of the cohort ris continously folowed
Hypothesis : High serum lithium levels are a cause of subsequent mental illness.
Take a cohort of say 1000 personswho are free of mental disease, collect their blood sample, preserve them in cold storage
CASE-COHORT STUDIES
CASE-COHORT STUDIESAdvantages: Recall bias is eliminated. If abnormalities in biologic characteristics such as laboratory
values are found, because the specimens were obtained years before the development of clinical disease, it is more likely that these findings represent risk factors or other premorbid characteristics than a manifestation of early, subclinical disease. When such abnormalities are found in the traditional case-control study, we do not know whether they preceded the disease or were a result of the disease.
More economical to conduct. It is possible to study different diseases (different sets of
cases) in the same case-cohort study using the same cohort for controls.
ADVANTAGES AND DISADVANTAGES OF CASE-CONTROL STUDIES
Advantages Disadvantages
Efficient for the study of rare diseases
Risk of disease cannot be estimated directly
Efficient for the study of chronic diseases
Not efficient for the study of rare exposure
Tend to require a smaller sample size than other designs
More susceptible to selection bias than alternative designs
Less expensive than alternative designs
Information on exposure may be less accurate than that available in alternative designs
May be completed more rapidly than alternative designs
SUMMARY
Review of research question and confirm that case -control study is the right design.
Specify the total population and actual (study) population.
Specify the major study variables (exposure,outcome,confounding factors) and their ‘scales’ of measurement(dichotomous etc)
Calculate the sample size.
Specify the selection criteria of cases
• Well suited for diseases which have a long latent period(e.g. cancers, AIDS, MI, CVA etc.)
• Well suited for an outcome which is ‘rare’• Well suited for conditions in which medical care is
usually sought• Helps in examining multiple etiologic factors - once
we have the cases of the disease, we can take history of all the factors that we feel may be risk factors
• Reasonably good for diseases that have a “relatively rapid onset” and are usually hospitalised (e.g. most of the acute infections; injuries etc.)
SUMMARYSpecify the selection procedure for controls
Specify the procedures of measurement and specially take care to ensure validity and reliability
Do a pilot study on 5 to 10 cases and controls
Conduct the study
Analysis of data
COHORT STUDY Forward looking ,incidence , longitudinal, prospective
study or follow up study Cohort = Group of people who share a common
characteristic or experience within a defined time period(age, occupation ,exposure etc).
Cohort study: Cohort studies are observational studies in which the investigator determines the exposure status of subjects and then follows them for subsequent outcomes
Quantified with relative risk/incidence rates/attributable risk
Cohorts are identified prior to the appearance of the disease under investigation.
BASIC FRAME WORK In cohort study the exposure has occurred , but the
disease has not.
Cohort With disease
Without disease
Total exposure
Exposure (etiologic factor)
a b a + b
Non- Exposure
c d c + d
a/(a + b) - Incidence of disease in exposed
c/( c + d)- Incidence of disease in non exposed if a/(a + b )> c/ (c + d) It would suggest that the disease and suspected cause are associated.
GENERAL CONSIDERATION Cohorts must be free from the disease under study. Study and control group must be easily susceptible
to the disease under study. Both the groups must be comparable in respect to
all the possible variables which may influence the frequency of the disease.
The diagnostic and eligibility criteria of the disease must be defined before hand.
Groups are then followed , under the same identical conditions, over a period of time to determine the outcome of the exposure.
TYPES OF COHORT STUDIES
define population
Non randomization
exposed Non exposed
diseased Not diseased
diseased
Not diseased
2000
2010
2020
1987
1997
2007
RetrospectiveProspective
combined
1987 2007 2017
ELEMENTS OF COHORT SELECTION OF STUDY SUBJECT OBTAINING THE DATA ON THE EXPOSURE. SELECTION OF THE COMPARISION GROUP. FOLLOW UP ANALYSIS
SELECTION OF STUDY POPULATION
SELECTION OF STUDY COHORT Special Exposure Groups (e.g. radiologists for
studies on effect of radiation; ANC cases having PIH for studying the outcome of pregnancy, etc.)
Cohort defined on basis of geographical or administrative boundaries (e.g. people living in a given state or district like Framingham heart study). The special advantage of such cohort is that the same group will give an exposed as well as unexposed (comparison) cohort.
Groups offering special resources (e.g. all registered doctors can be followed up for development of IHD after recording their physical activity levels.
OBTAINING DATA ON THE EXPOSURE
DATA External Sources Internal Sources
Exposure Hospital records Questionnaires, physical examinations, and/or blood tests, other diagnostic tests
Event Disease registries, death certificates, physician and hospital records
Questionnaires, physical examinations, and/or blood tests, other diagnostic tests
Confounder Hospital records registries
Questionnaires, physical examinations
SELECTION OF THE COMPARISON POPULATION Internal Control Group
Exposed and non-exposed in
the same Study population
(Framingham study) Minimise the differences
between exposed and non-
exposed External Control Group
When information on degree
of exposure is not available
chose another group, another
cohort (smokers and non
smokers)
General Population: If none of the
above comparison is available than
the mortality experience of the
exposed group is compared with the
mortality experience of the general
population in the same geographic
area as the exposed people.
E.g. comparison of frequency of
cancer among uranium mine
workers with the rate in general
population in same geographic area.
FOLLOW UP One of the problem in cohort studies is the regular
follow up of the participants. Therefore , at the start of the study, methods
should be devised depending upon the outcome to be determined (morbidity or Death) to obtain the data assessing the outcome.
Routine surveillance of
death records.
Review physician and
hospital records
Mailed questionnaires
, telephone calls, periodic home visits.
Periodic medical
examination of each
member of the cohort.
Death.Change of residence.Migration.Withdrawal from occupation etc.
Procedures:
EPIDEMIOLOGIC MEASURES OF ASSOCIATION Absolute comparison
Risk difference I exposed - I unexposed
Measures public health problem caused by the exposure
Relative comparisonRelative RiskOdds Ratio
RR=I exposed / I unexposed
Measures strength of an association
ANALYSIS DATA ARE ANALYSED IN TERMS OF
a) Incidence rates of outcome among exposed and non- exposed.
b) Estimation of risk.
(i) relative risk
(ii) attributable risk
INCIDENCE RATESCigarett
e smokin
g
Develop CHD
Did not develop
CHD
Total Incidence
Yes 70(a)
6930 (b)
7000 (a + b )
70/7000=10 per
1000
No 3(c)
2997 (d)
3000 (c +d)
3/3000=1 per 1000
ESTIMATION OF RISK R. R = incidence of disease (or Death) among exposed
incidence of disease (or Death) among non- exposed
Cigarette
smoking
Develop CHD
Did not develop
CHD
Total Incidence
Yes 70(a)
6930 (b)
7000 (a + b )
70/7000
0.01
No 3(c)
2997 (d)
3000 ( c +
d )
3/3000.001
RR= a/a+b = 70/7000 = 10 c/c+d 3/3000
INTERPRETATION OF RELATIVE RISK AND RATE RATIO RR=1 = No association between exposure and disease
incidence rates are identical between groups RR=> 1 = Positive association
exposed group has higher incidence than non-exposed group
RR=< 1 = Negative association or protective effect. non-exposed group has higher incidence than exposed
or exposed group has lower incidence than non-exposed e.g. RR 10% / 20% = 0.5 it would indicate that if one smokes, the risk of getting IHD is 10%; on the other hand if one does not smokes, the risk is 20%. Smoking thus reduces the risk of getting IHD by half.
MEASURES OF DIFFERENCE Risk difference =I exposed- I non exposed Attributable risk percent Population attributable risk percent.
ATTRIBUTABLE RISK PERCENT
Incidence
Exposed Unexposed
Iexposed – Iunexposed
I = Incidence= ( Iexposed-I unexposed)x 100
Iexposed
ATTRIBUTABLE RISK PERCENT
Attributable risk in our example:AR=( .01-.001/.01)x 100=90%
It indicates to what extent disease under study can be attributed to exposure. If smoking is given up then there will be 90% reduction in CHD among smokers.
Cigarette
smoking
Develop CHD
Did not develop
CHD
Total Incidence
Yes 70(a)
6930 (b)
7000 (a + b )
70/7000
0.01
No 3(c)
2997 (d)
3000 ( c +
d )
3/3000.001
The limitation of AR% is that it tells us the quantum of reductionin the disease that would be achieved in the “exposed” group if“exposure” was given up by them. However, it does not tell usabout the reduction that will occur in the “total population”
POPULATION ATTRIBUTABLE RISK Population attributable risk percent
Proportion of disease in the study population that could be eliminated if exposure is removed
Incidence in total population – Incidence in unexposed incidence in total population
{(73/10,000)-(3/3000)}/73/10,000=.86 PAR%=86%
BIASES IN COHORT STUDY Measurement (Ascertainment) bias : For obviating this, inform all
subjects of both groups well in advance of the dates and timings of medical examination and ensure that both the groups are examined by observers who have similar type of training and using similar type of instruments and techniques.
Observer bias : This occurs because the investigator is aware about the fact as to which subject is ‘exposed’ and who is not exposed. For obviating this, if possible, ‘blind’ the observer to the exposure status, the details of exposure being known only to another co - worker who is, himself, not making any observation regarding ascertainment of outcome.
Cross over bias : This may happen because those having the exposure (e.g. smokers) may cross over to the non exposed group (i.e. become non smokers) and vice versa. Periodic evaluation of both the groups as regards level of exposure, making record entries and subsequent adjustments in the data analysis can help overcoming this problem.
‘Loss to follow up’ bias : Some subjects in any case are likely to be lost to follow up / drop out.
ADVANTAGES DISADVANTAGES
Incidence can be calculated
Several possible outcomes related to exposure can be studied simultaneously.
Cohort studies provide a direct estimate of R.R
Dose – response ratio can also be calculated.
• Large No. of population.• Very lengthy- takes very long
time to complete.• Certain administrative.
• Loss of experience staff.• Loss of funding.• Extensive record keeping.
Selection of comparison group- limiting factor
There may be changes in study methods or Diagnostic Criteria of the Disease over the prolonged period.
Cohort studies are expensive. The study may itself alter the
patients Behavior.
FRAMINGHAM HEART STUDY Best-known cohort studies is the Framingham Study of
cardiovascular disease. Started in 1948. Framingham is a town in Massachusetts, about 20
miles from Boston. Residents between 30 and 62 years of age were
considered eligible for study. 1971 enrolled a second generation of participants. In April 2002, a third generation was enrolled in the
core study.
FRAMINGHAM HEART STUDY
Hypothesis: Incidence of CHD increases with age Hypertension develop CHD Elevated cholestrol is associated with ed CHD Tobacco smoking and habitual use of alcohol increased CHD Increased physical activity a/w with decreased incidence of
CHD Increased Body weight inceases incidence of CHD Diabetes increases incidence of CHD
New coronary events were identified by examining the study population every 2 years and by daily surveillance of hospitalizations at the only hospital in Framingham.
: contd..
FRAMINGHAM HEART STUDY Results: 1960s: Cigarette smoking Increased cholesterol and
elevated blood pressure obesity increases risk of heart disease. Exercise decreases risk of heart disease.
1970s: Elevated blood pressure increases risk of stroke. Postmenopausal women risk of heart disease is increased compared with who are premenopausal.
1980s High levels of HDL cholesterol reduce risk of heart disease.
1990s: Elevated blood pressure can progress to heart failure. At 40 years of age, the lifetime risk for CHD is 50% for men and 33% for women.
contd...
FRAMINGHAM HEART STUDY 2000s “High normal blood pressure" increases risk of
cardiovascular disease (high normal blood pressure is called prehypertension in medicine; it is defined as a systolic pressure of 120–139 mm Hg and/or a diastolic pressure of 80–89 mm Hg). Lifetime risk of developing elevated blood pressure is 90%. Serum aldosterone levels predict risk of elevated blood pressure. Lifetime risk for obesity is approximately 50%.
contd...
DIFFERENCES
SUMMARYSpecify the research question, objectives and background significance, confirm cohort study is to be done
Specify the variables of interest and their scales of Measurement (Exposure variable, Outcome variable, confounders)
Specify the exclusion criteria ( e.g. like to restrict the study to males)
Calculate the sample size
Select the study cohort(Special Exposure Groups , on basis of geographical or administrative boundaries)
• Where there is good evidence of association between exposure and disease, as derived from clinical observation and supported by descriptive and case –control studies.
• When exposure is rare, but the incidence of disease is high among exposed.
• When attrition of study population can be minimized e. g. follow up is easy , cohort is stable.
• When ample funds are available.
Select the study cohort
Select the comparison cohort (Ext. group,Int. group)
Specify the sampling procedure ( simple random or by systematic random sampling method).
Exclude the disease or outcome of interest in both the exposed and unexposed cohort groups
Obtain data on exposure level
Obtain Data on all Potential confounding factors
Consider matching (matching is not important , if eligible then frequency matching )
Follow up and ascertainment of ‘outcome’ of interest
Analysis
REFERENCES Text book of PSM 19th ed by K. Park Lange Medical Epidemiology 4th by Raymonds S
Greenberg , Stephen R Daniels ,John William Elley
Epidemiology by Leon Gordis. Textbook of Public Health and community
medicine by Rajvir Bhalwar ,Rajesh Vaidya, Reena Tilak
http://en.wikipedia.org/wiki/Cohort_(statistics)
THANK YOU