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?Question answered: "what will happen?" ? Prospective/forward ? Retrospective / backwards ? Ambidirectional cohort ( Both retrospective and prospective) ? e.g. Framingham study of cardiovascular disease: Started in 1948, 6000 citizens participated, followed for 20 years (study in 1970 by Gordon and Kannel) ? Possible uses: ? Typical cohort study ? Outcome assessment (patient outcomes: economic, functional, satisfaction, QOL, ..) ? Historical Cohort studies/AKA Retrospective cohort: Relies on prospective records collected (If accurate) - still forward in time in the past

The defining characteristic of all cohort studies is that they track people forward in time from exposure to outcome. Data collection may be prospective or retrospective. Ex. Contraceptives and DVT. Lancet 2002; 359: 57-61

Research in Reverse ?In a case-control study the study group is defined by the outcome (e.g. presence of a disease), not by exposure to a risk factor. ?The study starts with identification a group of cases (individuals with a particular health outcome) in a given population and a group of controls (individuals without the health outcome) ?The frequency of exposure to a potential risk factor is then compared between cases and controls. ?If the frequency of exposure is more common among cases than controls, the exposure may be a risk factor for the outcome under investigation. ?Designed to help determine if an exposure is associated with an outcome (i.e., disease or condition of interest). ?In theory, the case-control study can be described simply. ? First, identify the cases and the controls ?Then, look back in time to learn which subjects in each group had the exposure(s), ?Then compare the frequency of the exposure in the case group to the control group. ? It is always retrospective because it starts with an outcome then traces back to investigate exposures

As with all epidemiological investigations the beginning of a casecontrol study should begin with the formulation of a clearly defined hypothesis. ? Case definition ?It should be clearly defined at the onset of the study to ensure that all cases included in the study are based on the same diagnostic criteria. ? Source of cases ?The source of cases needs to be clearly defined. ? The first step in the selection of cases is the formulation of case definition. ? usually based on a combination of signs and symptoms, physical and pathological examinations, and results of diagnostic tests. ? Case identification and enrolment. ? Typical sources for identifying cases are hospital or clinic patient rosters, death certificates, special surveys, and reporting systems such as cancer or birth defects registries. ? Investigators consider both accuracy and efficiency in selecting a particular source for case. ? The goal is to identify as many true cases of disease as quickly and cheaply as possible. ?Selection of cases ?Case-control studies may use incident or prevalent cases. ?Incident cases ?comprise cases newly diagnosed during a defined time period. ?The use of incident cases is preferential, as the recall of past exposure(s) may be more accurate among newly diagnosed cases. ?In addition, the temporal sequence of exposure and disease is easier to assess among incident cases. ? Selection of cases ? Case-control studies may use incident or prevalent cases. ? Prevalent cases ? Comprise individuals who have had the outcome under investigation for some time. ? The use of prevalent cases may give rise to recall bias as prevalent cases may be less likely to accurately report past exposures(s). ? The interpretation of results based on prevalent cases may prove more problematic, as it may be more difficult to ensure that reported events relate to a time before the development of disease rather than to the consequence of the disease process itself. ? E.g, individuals may modify their exposure following the onset of disease

?The controls provide an estimate of the exposure rate that would be expected to occur in the cases if there was no association between the study disease and exposure. ? Individuals selected as controls should be ?free of the disease ?similar to the cases in regard to the possibility of having past exposure during the time period of risk. ? Controls must be sampled independently of exposure status. ?Exposed and unexposed controls should have the same probability of selection. ? In case-control studies where cases are hospital based, it is common to recruit controls from the hospital population. ?However, the choice of controls from a hospital setting should not include individuals with an outcome related to the exposure being studied. For example In a case-control study of the association between smoking and lung CA, the inclusion of controls being treated for a condition related to smoking (e.g. chronic bronchitis) may result in an underestimate of the strength of the association between the exposure (smoking) and outcome (lung CA) ?Case-control studies are often used for uncommon outcomes, ??investigators often have a limited number of cases. ?In this situation the statistical power of the study can be increased somewhat by enrolling more controls than cases. ? Ratios greater than 4:1 have little additional impact on power. ? However, if the data on controls is easily obtained, there is no reason to limit the number of controls. ?Can be 1:1, 1:2, 1:3, 1:4

?The process of making a study group and a comparison group similar or identical with respect to their distribution of extraneous factors ?This can be done by ?by individual matching (e.g. for each case, choose a control of the same age and gender) or ?by frequency matching (e.g. if there are 25 male cases in the 30- 34 age-group then choose the same number of male controls for this age-group). ?Case-control studies are used to investigate the risk of disease in relation to a wide variety of exposures, ?lifestyle, occupation, environment, genes, diet, reproduction, and the use of medications. ?Sources available for obtaining exposure data include ?in-person and telephone interviews; ?self-administered questionnaires; ?preexisting medical, pharmacy, registry, employment, insurance, birth, death, and environmental records; and ?biological specimens. ? Susceptible to bias introduced due to poor study design or during the collection of exposure and outcome data. ? Differential reporting of exposure information between cases and controls based on their disease status. ? Cases and controls may recall past exposure differently (Recall Bias) ? Similarly, the recording of exposure information may vary depending on the investigator's knowledge of an individual's disease status (interviewer/observer bias). ? Temporal bias (reverse causality) may also occur. When trying to establish a link between exposure and outcome, it must be clear that the exposure occurred before the disease of interest

? The odds ratio (OR) is used in C-C studies to estimate the strength of the association between exposure and outcome. ? It is not possible to estimate the incidence of disease ? The results of a C-C study can be presented in a 2x2 table

? The OR is a measure of the odds of exposure in the cases, compared to the odds of exposure in the control group. ? Calculation of the OR from a hypothetical case-control study of smoking and cancer of the pancreas among 100 cases and 400 controls

individuals with cancer of the pancreas (cases) are 4.5 times more likely to have smoked than those without the disease

? OR = 1 ? The odds of exposure among cases = the odds among the controls. ? Exposure does not appear to be a risk factor. ? OR > 1 ? Larger odds of exposure among the cases than among the controls. ? Cases have a higher odds of having been exposed in the past. ? Exposure appear to increase risk of disease. ? OR < 1 ? Smaller odds of exposure among cases as compared to controls, ??Controls have a higher odds of having been exposed. ? This situation illustrates a protective factor; exposure appears to reduce risk of disease. Advantage ? Cost-effective relative to other studies. ? No long follow up period (as compared to cohort studies). ? Efficient for the study of diseases with long latency periods. ? Efficient for the study of rare diseases. ? Good for examining multiple exposures Disadvantage ? Selective recall (Recall bias) ? Mortality bias if prevalent rather than incident cases. ? Temporal relationship unclear. ? Difficulty in defining control group. ? Not optimal for rare exposures. ? A case-control study to assess the relation between stroke and cigarette smoking. 101 stroke patients were compared with 137 healthy controls. 71 of the stroke patients reported ever smoked compared to 36 of the controls reported ever smoked ? Is there is relation between stroke and cigarette smoking? Explain your answer. ? Construct a 2 x 2 table Stroke +ve Stroke -ve Total Ever smoked +ve 71 36 107 Ever smoked - ve 30 101 131 Total 101 137 238 ? Calculate the odds ratio (OR) OR= 71x101/36x30 = 7171/1080=6.6 ? Interpretation: stroke patients are 6.6 more probable to have ever smoked compared to controls

? A study where the cases and controls are selected from individuals within an established cohort study. ?It is thus said to be 'nested' within the cohort study. ?Cases of a disease that arise within the defined cohort during the follow up period are identified, then a specified number of matched controls who have not developed the disease are selected from the same cohort. ?Analysis is carried out in the same way as a normal case control, with calculation of odds ratios. ?Strengths of nested case-control studies ?Relatively cheap and easy to conduct. ?Data related to exposure and confounding have already been collected. ?Can utilize the baseline data on exposure and confounding collected before the onset of disease, which reduces the ?potential for recall bias ?uncertainty regarding the temporal sequence between exposure and disease onset. ? Case-control studies have been used in a variety of situations to evaluate possible causes of rare conditions. ? Classic examples include the investigation of cases of childhood leukaemia near the nuclear procession plant at Sellafield in Cumbria

?In a cross-sectional study, data are collected on the whole study population at a single point in time to examine the relationship between disease (or other health related state) and other variables of interest. ?They provide a snapshot of the frequency of a disease or other health related characteristics in a population at a given point in time. This methodology can be used to assess: ? Burden of illness and risk factors ? Service needs ? Hypothesis generation ? Estimate prevalence of disease at a single time point. ? Estimate prevalence of risk factors at a single time point. ? provide a "snapshot" of diseases and risk factors simultaneously in a defined population ??A cohort study is the best way to identify incidence and natural history of a disease, and can be used to examine multiple outcomes after a single exposure ?Also called follow-up or incidence studies ?Begin with sample "Healthy Cohort" (i.e., subjects without the outcome yet) ?Start with Exposure status, then compare subsequent disease experience in exposed vs. unexposed. ?Purpose: Estimate the incidence of disease or estimate association between exposure and disease ?The control group (unexposed) should be similar in all important respects to the exposed, with the exception of not having the exposure

This type of observational study is the one that most closely resembles intervention studies, except that allocation of subjects to the exposure is

?This type of study can be done by going ahead in time from the present (prospective cohort study) or, alternatively, by going back in time to comprise the cohorts and following them up to the present (retrospective cohort study) ? Prospective studies: carried out from the present time into the future, can be tailored to collect specific exposure data, but there may be a long wait for events to occur, particularly where the outcome of interest is associated with old age. ? They can be expensive and are prone to high dropout rates. ?Retrospective Studies (Historical Cohort): look at medical events from some time point in the past up to the present time. ?The advantage is that the information is available immediately. ?There may for such studies, however. The defining characteristic of all cohort studies is that they track people forward in time from exposure to outcome. ? Disadvantages ?The difficulty in tracing subjects ?The quality of recorded information. ? Selection of study groups ? The aim of a cohort study is to select study participants who are identical with the exception of their exposure status. ? At the beginning of the study; all study participants must be free of the outcome under investigation and have the potential to develop the outcome under investigation. ? If the exposure is common, the study population can be selected before classifying individuals ? If the exposure is rare, the study population may be chosen on the basis of exposure, to ensure sufficient exposed individuals are enrolled. ?Measuring exposure ? Levels of exposure (e.g. packs of cigarettes smoked per year) are measured for each individual at baseline at the beginning of study and assessed at intervals during the period of follow-up. ?When several exposures are being considered simultaneously, the non-exposed group should comprise all those with none of the risk factors under investigation. ? Exposure data may be obtained from a number of sources including medical or employment records, standardized questionnaires, interviews and by physical examination. ?Measuring outcome ?Outcome measures may be obtained from various sources including routine surveillance of cancer registry data, death certificates, medical records or directly from the participant. ?Note that the method used to ascertain outcome must be identical for both exposed and unexposed groups to avoid measurement bias. ??Information on outcomes should be collected by members of the study team who are blind to participants' exposure status, to reduce the risk of observer bias. ?Methods of follow up ?The follow up is a major challenge, and it may take many years for a sufficient proportion of participants to have reached an outcome. ?A great deal of cost and time is required to ensure adequate followup of cohort members and to update measures of exposures and confounders, as well as monitoring participants' health outcomes. ?Failure to collect outcome data for all members of the cohort will affect the validity of study results

? A major source of potential bias in cohort studies ? Cohort members may die, migrate, change jobs or refuse to continue to participate in the study. ? In addition losses to follow up may be related to the exposure, outcome or both. ? For example individuals who develop the outcome may be less likely to continue to participate in the study. ? The degree to which losses to follow up are correlated with either exposure or outcome can lead to serious bias in the measurement of effect of exposure and outcome

?Related to the degree of accuracy with which subjects have been classified with respect to their exposure or disease status. ? Differential misclassification, when one group of participants is more likely to have been misclassified than the other, can lead to an over- or underestimate of the effect between exposure and outcome ?Analysis of a cohort study uses the ratio of either the risk or rate of disease in the exposed cohort, compared with the rate or risk in the unexposed cohort. ?Relative Risk {Risk(Rate) Ratio} ?Comparing disease occurrence among exposed with disease occurrence among comparison group (usually unexposed) in a ratio measure. Risk in exposed

Risk in unexposed ? Relative Risk=

?The relative risk can be calculated as follows

?The RR of 15 indicates that the risk of cancer of the pancreas is 15 times higher among smokers than non-smokers ? If RR = 1: Risk in the exposed equal to risk in unexposed (no association) ? If RR > 1: Risk in exposed greater than risk in unexposed (positive association; possibly causal) ? If RR < 1: Risk in exposed less than risk in unexposed (negative association; possibly protective)

Advantage ? Temporal relationship clear. ? Can study course of disease development. ?Good for rare exposures. ?Decreases potential for many biases since disease has not occurred at time of classification. Disadvantage ?Time-consuming, expensive. ?Loss to follow-up and missing data - ex; drop-outs, attrition, migration. ?Not suitable for rare diseases. A cohort study was conduct to evaluate the relation between cigarette smoking and MI. The study was performed on 789 individuals of who 267 were cigarette smokers. MI was diagnosed in 157 smokers compared to 209 non-smokers. Is there is relation between myocardial infarction and smoking? Explain your answer. o Construct a 2 x 2 table MI +ve MI -ve Total Cig Smok +ve 157 267 Cig Smok -ve 209 522 Total 789 o Calculate the incidence of myocardial infarction among smokers, nonsmokers ??I exp= 157/267= 58.8% ??I un-exp= 209/522= 40.0% o Calculate the relative risk and interpreted the findings ? RR= Iexo/Iun-exp= 58.8/40.0 ? 1.47 ? Smokers are 1.5 times more risky to develop MI compared

Sir Richard Doll's study of the hazards of cigarette smoking ? One of the best examples of a prospective cohort study ??To investigate the relationship between smoking and lung cancer. ? They followed up 40 000 British doctors (divided into four cohorts): ??non-smokers, and light, moderate and heavy smokers. ? Death was the outcome they recorded. ? They used both all cause death (any death) and cause specific death (death from a particular disease). ? Results in 1964, showed a substantial excess in both mortality from lung cancer and all cause mortality in smokers, with a "dose-response" relation

?Uncontrolled trials

• Experimental drug or procedure compared with another, with a placebo, or with the standard procedure
• Greater validity ?Trials with independent concurrent controls ?Double or single blind ?Best is randomized assignment ?Same point in time ?These includes 4 types of controlled studies A. Randomized controlled trials (RCT): ?The epitome of all research designs ?Provides the strongest evidence of concluding causation ?Best insurance that results are due to the intervention

Miss : Haneen Dhaidel , Fundemental methods research , Fall 2023 ?SINGLE-BLIND CLINICAL TRIAL: Trial in which the subject, but not the observer, does not know which of the possible treatments he is receiving.prevalence: ?In analytical cross-sectional studies, the OR can be used to assess the strength of an association between a risk factor and health outcome of interest

Advantages ?Quick and cheap ?Able to measure prevalence for all factors under investigation ?Multiple outcomes and exposures can be studied ?Examine associations ?Good for generating hypotheses Disadvantages ?Snapshot in time ?Temporal associations not clear ?Selection bias ?Over-representation of cases with long duration ?Underestimate of cases with short duration.Differentially administer co-interventions ?????????????????????????????????????

 A study design is the process that guides researchers on how to collect, analyze and interpret observations.
 It is a specific plan or protocol for conducting the study,
which allows the investigator to translate the conceptual hypothesis into an operational one
 Depending on the existing state of knowledge about the problem, different types of questions may be asked which require different 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.

Several classifications of study types are possible, depending
on what research strategies are used.
Experimental (Intervention) studies
The researcher manipulates objects or situations and measures the outcome of his manipulations
Observational studies
The researcher just observes and analyses researchable objects or situations but does not intervene
Case Report
Case Series

Depends on:
Research Questions
Research Goals
Researcher Beliefs and Values
Researcher Skills
Time and Funds
It is also related to:
Status of existent knowledge
Occurrence of disease
Duration of latent period
Nature and availability of information
Available resources

The researcher manipulates a situation and measures the effects of this manipulation.
Usually (but not always) two groups are compared,
One group in which the intervention takes place (e.g. treatment with a certain drug) ---- Intervention Group
Another group that remains ‘untouched’ (e.g. treatment with a placebo)---- Control Group
The two categories of intervention studies are:
Experimental studies and
Quasi-experimental studies
TYPES OF INTERVENTION

The intervention being tested is allocated to a group of two
or more study subjects (individuals, households, communities).
Subjects are followed prospectively to compare the intervention vs. the control (standard treatment, no treatment or placebo).

• Randomized vs Non-randomized trials
• Controlled trials vs Uncontrolled trials

 
General outline of a two-armed randomized  

A placebo-controlled randomized trial might compare the effect of vitamin E treatment in schizophrenia patients (the treatment group) against the effects of a placebo on a separate group of schizophrenia patients (the control group).
An active-controlled randomized trial might compare general anesthesia (GA) group alone or GA combined with Thoracic epidural anesthesia (TEA) to determine the beneficial effects of TEA on pulmonary function in elderly patients undergoing CABG surgery

 Random allocation of subjects to the experiment and control groups.
 Each subject has an equal chance of being assigned to any group in the study
 Randomization avoids bias and confounders by eliminating baseline differences in risk between groups.
 The study groups are similar in all characteristics except for the intervention
 Randomization, if done properly, should make both groups similar in terms of the distribution of risk factors,
 regardless of whether these risk factors are known or unknown
 Systematic allocation
Participants are allocated into study groups alternately, or on alternate days.
It may be possible for the investigator to manipulate the process, if they Favor one study arm over another (selection bias).
Simple randomization
E.g, computer generated random number tables or tossing a coin.
It may result in different numbers of patients in each group (rarely used)

 Block randomization
 Participants are allocated in blocks of 4
 to ensure that the numbers of participants assigned to each group is equally distributed
 Commonly used in smaller trials.
 Stratified randomization
 Prior to randomization, participants are separated into different subgroups
or strata, for example sex or age.
 Equal numbers are then randomly allocated to each treatment arm from within the strata.
 ensure that important baseline variables (potential confounding factors) thought to be associated with the outcome are evenly

Sometimes in clinical trials participants, and sometimes investigators as well, are made unaware of whether they are part of the treatment or control group.
Single-blinded: only study subjects are unaware of their treatment status
Double-blinded: both the participants and the investigators are blinded as to the treatment status of the participants.
Triple blinded trial : subjects, investigators, and independent statisticians are kept unaware of subject treatment status.

 Participants are less likely to
 Have biased psychological or physical responses to intervention
 Not to comply with trial regimens
 Less likely to seek additional adjunct interventions
 Less likely to leave trial without providing outcome data
 Trial investigators are less likely to
 Transfer their attitudes to participants
 Differentially administer co-interventions
 Differentially adjust dose
 Differentially encourage or discourage participants to continue trial

 Clinical equipoise
 there must be sufficient doubt about the particular agent being tested to allow withholding of it from half the subjects, and at the same time there must be sufficient belief in the agent's potential to justify exposing the remaining half of all willing and eligible participants. (Clinical equipoise).
 There must be sufficient belief that the intervention under investigation is safe.
 Informed consent is essential. Study subjects must
 understand that they are participating in an experiment and that in a placebo-controlled trial they may receive an inactive product. be informed of the aims, methods and potential benefits or hazards of participating in the trial.

Careful consideration should be given to what intervention is given to the control group.
For example, if an effective treatment already exists, participants in the control group should not
receive a placebo, depriving them of this.
 Study participants shouldn’t suffer as a consequence of a RCT.
 Most RCTs incorporate a data monitoring and safety committee who are independent of the investigators

Frequency of Various Types of Physician-Industry Relationships

The analysis of RCT data is focused on estimating the size of
the difference in predefined outcomes between the intervention groups.
The main measure of effect obtained is the rate or risk ratio.
 Rate or risk among intervention group/ Rate or risk among
control group

 Loss to follow up
 Neither randomization nor blinding can prevent differential loss to follow up, or more subjects dropping out in one treatment group than in another.
 Bias is introduced if the rate of loss to follow-up is correlated with the exposure and/or the outcome.
 Non-compliance
 Diminished interest or lack of compliance in the prescribed intervention
 Crossovers
 Switching to the other treatment at the midpoint of the trial
 Negates the benefit of randomization and introduces bias

Advantage
The “gold standard” of research designs
Randomization - balance of confounding factors
Uniform collection of data
Protocol procedures and
interventions specified
Blinding
Disadvantage
 Large number of participants
 Financial costs
Ethics (limited to interventions that are thought beneficial
Subjects may not comply with interventions
(dropout)
Long time for conclusion

Crossover trials
Each subject acts as their own control, and receives all the treatments under investigation in sequence.
 Random allocation determines the sequence in which each participant receives the treatments.
This type of trial may be used when the intervention does not have long-term effects.
Advantage: the groups are as similar as possible.
In crossover trials it is common to have a 'washout period'
 no treatment is given between each intervention to avoid the possibility of a residual effect from the previous treatment.
Factorial trials
 A factorial trial is where two or more interventions are evaluated simultaneously compared with a control group in the same trial. This type of RCT is commonly used to evaluate interactions between interventions.

 Community or cluster-randomized controlled trials
 Involve groups of individuals or communities, as opposed to individuals.
 Groups or communities are randomized to receive the intervention or standard/no treatment.
 This type of study design may be used to evaluate preventative health services such as smoking cessation programs.
 For example all patients attending a single general practice may be allocated to receive the new program, whilst those at another practice will receive standard care.
 In this sort of trial, intra-cluster correlation needs to be taken into account in assessing effect size and sample size.

It is one that looks a bit like an experimental design but lacks
the key ingredient -- random assignment.
Often referred to as "queasy" experiments because they give
the experimental purists a queasy feeling.
With respect to internal validity, they often appear to be inferior to randomized experiments.
They are easily more frequently implemented than their randomized cousins

 A non-equivalent groups design
 An existing group of participants who receive a Tx & another existing group of participants to serve as a control or comparison group. Participants are not randomly assigned to conditions, but rather are assigned to the Tx or control conditions along with all the others in their existing group
 Pretest-posttest design
 A single group of participants is measured on the dependent variable both before and after the manipulation of the independent variable. The problem with pretest-posttest designs is that you cannot be completely sure that a change in the dependent variable was caused by the manipulation of the independent variable.
 One of the first RCTs to be carried out was the evaluation of streptomycin in the treatment of TB, published in 1948.
 Streptomycin treatment of pulmonary tuberculosis: a Medical Research Council investigation.
BMJ 1948;2:769-782.
 A non-randomized study published in 1980 evaluated the possible benefit of vitamin supplementation at the time of conception in women at high risk of having a baby with a neural tube defect. The investigators found that the vitamin group subsequently had fewer babies with neural tube defects than the placebo control group. The control group included women ineligible for the trial as well as women who refused to participate. As a consequence the findings were not widely accepted, and the Medical Research Council later funded a large randomized trial to answer to the question in a way that would be widely accepted (reference below).6
 MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research

 AKA Clinical Trials (Involve humans)
 Easier to identify (usually explicitly stated in the abstract)
 Two main categories of clinical trials:

1. Controlled trials


2. Uncontrolled trials

– Experimental drug or procedure compared with another, with a placebo, or with the standard procedure
– Greater validity
Trials with independent concurrent controls
Double or single blind
Best is randomized assignment
Same point in time
These includes 4 types of controlled studies
A. Randomized controlled trials (RCT):
The epitome of all research designs
Provides the strongest evidence of concluding causation
Best insurance that results are due to the intervention

Miss : Haneen Dhaidel , Fundemental methods research , Fall 2023
SINGLE-BLIND CLINICAL TRIAL:
Trial in which the subject, but not the observer, does not know which of the possible treatments he is receiving.
DOUBLE-BLIND CLINICAL TRIAL:
Trial in which neither the subject nor the observer know which treatment is being administered.
TRIPLE-BLIND CLINICAL TRIAL:
Clinical trial in which the participating subject, the observer-researcher and the researcher who analyzes the data do not know which treatment is being received

Assignment to either groups is not randomized
Opened to biases

Subject to bias (Hawthorne effect)
Can do crossover study (with washout period in between)
Patients work as control for them selves
Before and after testing

 Uses the results of another investigator’s research as a comparison
 Historical controls can also be used: for disease with no cures yet
 Specially when the other researcher is using the same out come measure , then comparison is much easier
 The researcher used the medication A ( and did before and after testing ) and I am suing the medication B, and compare to his results
 The answer is not just ABOUT THE EFFECTIVENESS OF MY MEDICATION, BUT IT IS ALSO ABOUT IF IT IS BETTER THAT THE MEDICATION USED IN THAT RESEARCH

 Investigator’s experience with the new drug or procedure is described but not formally compared with another one
 More likely to be used for interventions that are procedures rather than drug
 Uncontrolled study
 A clinical study that lacks a comparison (i.e., a control) group.

HTTPS://PMC.NCBI.NLM.NIH
.GOV/ARTICLES/PMC674338
7/

Marching Towards Outcomes

 The term cohort has military, not medical, roots.
A cohort was a 300–600-man unit in the Roman army; ten cohorts formed a legion.
A cohort study consists of bands or groups of persons marching forward in time from an exposure to one or more outcomes
They are observational studies in which the starting point is the selection of a study population, or cohort.
Information is obtained to determine which members of this cohort are exposed to the factor of interest.
The entire population is then followed up over time and the incidence of the disease in the exposed individuals is compared with the incidence in those not exposed.
A cohort study is the best way to identify incidence and natural history of a disease, and can be used to examine multiple outcomes after a single exposure
Also called follow-up or incidence studies
Begin with sample “Healthy Cohort” (i.e., subjects without the outcome yet)
Start with Exposure status, then compare subsequent disease experience in exposed vs. unexposed.
Purpose: Estimate the incidence of disease or estimate association between exposure and disease
The control group (unexposed) should be similar in all important respects to the exposed, with the exception of not having the exposure

This type of observational study is the one that most closely resembles intervention studies, except that allocation of subjects to the
exposure is

This type of study can be done by going ahead in time from the present (prospective cohort study) or, alternatively, by going back in time to comprise the cohorts and following them up to the present (retrospective cohort study)
 Prospective studies: carried out from the present time into the future, can be tailored to collect specific exposure data, but there may be a long wait for events to occur, particularly where the outcome of interest is associated with old age.
 They can be expensive and are prone to high dropout rates.

Retrospective Studies (Historical Cohort): look at medical events from some time point in the past up to the present time.
The advantage is that the information is available immediately.
There may for such studies, however.
The defining characteristic of all cohort studies is that
they track people forward in time from exposure to outcome.
 Disadvantages
The difficulty in tracing subjects
The quality of recorded information.

 Selection of study groups
 The aim of a cohort study is to select study participants who are identical with the exception of their exposure status.
 At the beginning of the study; all study participants must be free of the outcome under investigation and have the potential to develop the outcome under investigation.
 If the exposure is common, the study population can be selected before classifying individuals
 If the exposure is rare, the study population may be chosen on the basis of exposure, to ensure sufficient exposed individuals are enrolled.
Measuring exposure
 Levels of exposure (e.g. packs of cigarettes smoked per year) are measured for each individual at baseline at the beginning of study and assessed at intervals during the period of follow-up.
When several exposures are being considered simultaneously, the non-exposed group should comprise all those with none of the risk factors under investigation.
 Exposure data may be obtained from a number of sources including medical or employment records, standardized questionnaires, interviews and by physical examination.
Measuring outcome
Outcome measures may be obtained from various sources including routine surveillance of cancer registry data, death certificates, medical records or directly from the participant.
Note that the method used to ascertain outcome must be identical for both exposed and unexposed groups to avoid measurement bias.
Information on outcomes should be collected by members of the study team who are blind to participants’ exposure status, to reduce the risk of observer bias.
Methods of follow up
The follow up is a major challenge, and it may take many years for a sufficient proportion of participants to have reached an outcome.
A great deal of cost and time is required to ensure adequate followup of cohort members and to update measures of exposures and confounders, as well as monitoring participants’ health outcomes.
Failure to collect outcome data for all members of the cohort will affect the validity of study results

 A major source of potential bias in cohort studies
 Cohort members may die, migrate, change jobs or refuse to continue to participate in the study.
 In addition losses to follow up may be related to the exposure, outcome or both.
 For example individuals who develop the outcome may be less likely to continue to participate in the study.
 The degree to which losses to follow up are correlated with either exposure or outcome can lead to serious bias in the measurement of effect of exposure and outcome

Related to the degree of accuracy with which subjects have been classified with respect to their exposure or disease status.
 Differential misclassification, when one group of participants is more likely to have been misclassified than the other, can lead to an over- or underestimate of the effect between exposure and outcome
Analysis of a cohort study uses the ratio of either the risk or rate of disease in the exposed cohort, compared with the rate or risk in the unexposed cohort.
Relative Risk {Risk(Rate) Ratio}
Comparing disease occurrence among exposed with disease occurrence among comparison group (usually unexposed) in a ratio measure.
Risk in exposed

Risk in unexposed
 Relative Risk=

The relative risk can be calculated as follows

The RR of 15 indicates that the risk of cancer of the pancreas is 15 times higher among smokers than non-smokers
 If RR = 1: Risk in the exposed equal to risk in unexposed (no association)
 If RR > 1: Risk in exposed greater than risk in unexposed (positive association; possibly causal)
 If RR < 1: Risk in exposed less than risk in unexposed (negative association; possibly protective)

Advantage
 Temporal relationship clear.
 Can study course of disease development.
Good for rare exposures.
Decreases potential for many biases since disease has not occurred at time of classification.
Disadvantage Time-consuming, expensive.
Loss to follow-up and missing data – ex; drop-outs, attrition, migration.
Not suitable for rare diseases.

A cohort study was conduct to evaluate the relation between cigarette smoking and MI. The study was performed on 789 individuals of who 267 were cigarette smokers. MI was diagnosed in 157 smokers compared to 209 non-smokers.
Is there is relation between myocardial infarction and smoking? Explain your answer.
• Construct a 2 x 2 table
MI +ve MI –ve Total
Cig Smok +ve 157 267
Cig Smok -ve 209 522
Total 789
• Calculate the incidence of myocardial infarction among smokers, nonsmokers
I exp= 157/267= 58.8% I un-exp= 209/522= 40.0%
• Calculate the relative risk and interpreted the findings
 RR= Iexo/Iun-exp= 58.8/40.0 ≈ 1.47
 Smokers are 1.5 times more risky to develop MI compared

Sir Richard Doll’s study of the hazards of cigarette smoking
 One of the best examples of a prospective cohort study To investigate the relationship between smoking and lung cancer.
 They followed up 40 000 British doctors (divided into four cohorts): non-smokers, and light, moderate and heavy smokers.
 Death was the outcome they recorded.
 They used both all cause death (any death) and cause specific death (death from a particular disease).
 Results in 1964, showed a substantial excess in both mortality from lung cancer and all cause mortality in smokers, with a “dose-response” relation

 Framingham cardiovascular studies
 Following people living in the town of Framingham, Massachusetts
 Original cohort: 5,209 residents of Framingham, MA (1948)
 Offspring cohort: 5,124 children + spouses (1971)
 Framingham III: 3,500 grandchildren (ongoing)
 Identification of major risk factors for heart disease
 Much of our current knowledge about heart disease, such as the effects of diet, exercise, and common medications such as aspirin, is based on this longitudinal cohort study.
 The Whitehall studies
 In the UK, the Whitehall studies have followed cohorts of British civil servants, demonstrating how groups in the cohort with differing levels of a characteristic such as cholesterol subsequently have different rates of ischemic heart disease.

 Question answered: “what will happen?”
 Prospective/forward
 Retrospective / backwards
 Ambidirectional cohort ( Both retrospective and prospective)
 e.g. Framingham study of cardiovascular disease: Started in 1948, 6000 citizens participated, followed for 20 years (study
in 1970 by Gordon and Kannel)  Possible uses:
 Typical cohort study
 Outcome assessment (patient outcomes: economic, functional, satisfaction, QOL, ..)
 Historical Cohort studies/AKA Retrospective cohort: Relies on prospective records collected (If accurate) – still forward in time in the past

The defining characteristic of all cohort studies is that they track people forward in time from exposure to outcome. Data collection may be prospective or retrospective. Ex. Contraceptives and DVT.

Lancet 2002; 359: 57-61

Research in Reverse
In a case-control study the study group is defined by the outcome (e.g. presence of a disease), not by exposure to a risk factor.
The study starts with identification a group of cases (individuals with a particular health outcome) in a given population and a group of controls (individuals without the health outcome)
The frequency of exposure to a potential risk factor is then compared between cases and controls.
If the frequency of exposure is more common among cases than controls, the exposure may be a risk factor for the outcome under investigation.
Designed to help determine if an exposure is associated with an outcome (i.e., disease or condition of interest).
In theory, the case-control study can be described simply.
 First, identify the cases and the controls
Then, look back in time to learn which subjects in each group had the exposure(s),
Then compare the frequency of the exposure in the case group to the control group.
 It is always retrospective because it starts with an outcome then traces back to investigate exposures

As with all epidemiological investigations the beginning of a casecontrol study should begin with the formulation of a clearly defined hypothesis.
 Case definition
It should be clearly defined at the onset of the study to ensure that all cases included in the study are based on the same diagnostic criteria.
 Source of cases
The source of cases needs to be clearly defined.
 The first step in the selection of cases is the formulation of case definition.
 usually based on a combination of signs and symptoms, physical and pathological examinations, and results of diagnostic tests.
 Case identification and enrolment.
 Typical sources for identifying cases are hospital or clinic patient rosters, death certificates, special surveys, and reporting systems such as cancer or birth defects registries.
 Investigators consider both accuracy and efficiency in selecting a particular source for case.
 The goal is to identify as many true cases of disease as quickly and cheaply as possible.
Selection of cases
Case-control studies may use incident or prevalent cases.
Incident cases
comprise cases newly diagnosed during a defined time period.
The use of incident cases is preferential, as the recall of past exposure(s) may be more accurate among newly diagnosed cases.
In addition, the temporal sequence of exposure and disease is easier to assess among incident cases.
 Selection of cases
 Case-control studies may use incident or prevalent cases.
 Prevalent cases
 Comprise individuals who have had the outcome under investigation for some time.
 The use of prevalent cases may give rise to recall bias as prevalent cases may be less likely to accurately report past exposures(s).
 The interpretation of results based on prevalent cases may prove more problematic, as it may be more difficult to ensure that reported events relate to a time before the development of disease rather than to the consequence of the disease process itself.
 E.g, individuals may modify their exposure following the onset of disease

The controls provide an estimate of the exposure rate that would be expected to occur in the cases if there was no association between the study disease and exposure.
 Individuals selected as controls should be
free of the disease
similar to the cases in regard to the possibility of having past exposure during the time period of risk.
 Controls must be sampled independently of exposure status.
Exposed and unexposed controls should have the same probability of selection.
 In case-control studies where cases are hospital based, it is common to recruit controls from the hospital population.
However, the choice of controls from a hospital setting should not include individuals with an outcome related to the exposure being
studied.
For example
In a case-control study of the association between smoking and lung CA, the inclusion of controls being treated for a condition related to smoking (e.g. chronic bronchitis) may result in an underestimate of the strength of the association between the exposure (smoking) and outcome (lung CA)
Case-control studies are often used for uncommon outcomes, investigators often have a limited number of cases.
In this situation the statistical power of the study can be increased somewhat by enrolling more controls than cases.
 Ratios greater than 4:1 have little additional impact on power.
 However, if the data on controls is easily obtained, there is no reason to limit the number of controls.
Can be 1:1, 1:2, 1:3, 1:4

The process of making a study group and a comparison group similar or identical with respect to their distribution of extraneous factors
This can be done by
by individual matching (e.g. for each case, choose a control of the same age and gender) or
by frequency matching (e.g. if there are 25 male cases in the 30- 34 age-group then choose the same number of male controls for this age-group).
Case–control studies are used to investigate the risk of disease in relation to a wide variety of exposures,
lifestyle, occupation, environment, genes, diet, reproduction, and the use of medications.
Sources available for obtaining exposure data include
in-person and telephone interviews;
self-administered questionnaires;
preexisting medical, pharmacy, registry, employment, insurance, birth, death, and environmental records; and biological specimens.
 Susceptible to bias introduced due to poor study design or during the collection of exposure and outcome data.
 Differential reporting of exposure information between cases and controls based on their disease status.
 Cases and controls may recall past exposure differently (Recall Bias)
 Similarly, the recording of exposure information may vary depending on the investigator’s knowledge of an individual’s disease status (interviewer/observer bias).
 Temporal bias (reverse causality) may also occur. When trying to establish a link between exposure and outcome, it must be clear that the exposure occurred before the disease of interest

 The odds ratio (OR) is used in C-C studies to estimate the strength of the association between exposure and outcome.
 It is not possible to estimate the incidence of disease
 The results of a C-C study can be presented in a 2x2 table

 The OR is a measure of the odds of exposure in the cases, compared to the odds of exposure in the control group.

 Calculation of the OR from a hypothetical case-control study of smoking and cancer of the pancreas among 100 cases and 400 controls

individuals with cancer of the pancreas (cases) are 4.5 times more likely to have smoked than those without the disease

 OR = 1
 The odds of exposure among cases = the odds among the controls.
 Exposure does not appear to be a risk factor.
 OR > 1
 Larger odds of exposure among the cases than among the controls.
 Cases have a higher odds of having been exposed in the past.
 Exposure appear to increase risk of disease.
 OR < 1
 Smaller odds of exposure among cases as compared to controls, Controls have a higher odds of having been exposed.
 This situation illustrates a protective factor; exposure appears to reduce risk of disease.

Advantage
 Cost-effective relative to other studies.
 No long follow up period (as compared to cohort studies).
 Efficient for the study of diseases with long latency periods.
 Efficient for the study of rare diseases.
 Good for examining multiple exposures
Disadvantage
 Selective recall (Recall bias)
 Mortality bias if prevalent rather than incident cases.
 Temporal relationship unclear.
 Difficulty in defining control group.
 Not optimal for rare exposures.

 A case-control study to assess the relation between stroke and cigarette smoking. 101 stroke patients were compared with 137 healthy controls. 71 of the stroke patients reported ever smoked compared to 36 of the controls reported ever smoked
 Is there is relation between stroke and cigarette smoking? Explain your answer.
 Construct a 2 x 2 table
Stroke +ve Stroke –ve Total
Ever smoked +ve 71 36 107
Ever smoked – ve 30 101 131
Total 101 137 238
 Calculate the odds ratio (OR)
OR= 71x101/36x30 = 7171/1080=6.6
 Interpretation: stroke patients are 6.6 more probable to have ever smoked compared to controls

 A study where the cases and controls are selected from individuals within an established cohort study.
It is thus said to be ‘nested’ within the cohort study.
Cases of a disease that arise within the defined cohort during the follow up period are identified, then a specified number of matched controls who have not developed the disease are selected from the same cohort.
Analysis is carried out in the same way as a normal case control, with calculation of odds ratios.

Strengths of nested case-control studies
Relatively cheap and easy to conduct.
Data related to exposure and confounding have already been collected.
Can utilize the baseline data on exposure and confounding collected before the onset of disease, which reduces the
potential for recall bias
uncertainty regarding the temporal sequence between exposure and disease onset.

 Case-control studies have been used in a variety of situations to evaluate possible causes of rare conditions.
 Classic examples include the investigation of cases of childhood leukaemia near the nuclear procession plant at Sellafield in Cumbria

In a cross-sectional study, data are collected on the whole study population at a single point in time to examine the relationship between disease (or other health related state) and other variables of interest.
They provide a snapshot of the frequency of a disease or other health related characteristics in a population at a given point in time.
This methodology can be used to assess:
 Burden of illness and risk factors
 Service needs
 Hypothesis generation
 “Prevalence study” “Snapshot studies”
 Estimate prevalence of disease at a single time point.
 Estimate prevalence of risk factors at a single time point.
 provide a "snapshot" of diseases and risk factors simultaneously in a defined population
 Estimate association between disease and exposure at a single time point or. Unlike populations studied in cohort and case–control studies, cross-sectional study, populations are commonly selected without regard to exposure or disease status.

OnsetTime
of study
No direction of inquiry

 Descriptive
 It may be purely descriptive and used to assess the frequency and distribution of a particular disease in a defined population.
 E.g; a random sample of schools across Nablus may be used to assess the prevalence of asthma among 12-14 year olds.
 Analytical
 They can be used to investigate the association between a risk factor and a health outcome.
 Unable to draw valid conclusions about any association or possible causality (risk factors and outcomes are measured simultaneously)
 Choosing a representative sample
 A C-S study should be representative of the population
 For example, a study of the prevalence of DM among women aged 40-60 years in Town A should comprise a random sample of all women aged 40-60 years in that town.
 Sample Size
 It sufficiently large enough to estimate the prevalence of the conditions of interest with adequate precision.
 Sample size calculations can be carried out using sample size tables or statistical packages such as Epi Info.
Data collection
As data on exposures and outcomes are collected simultaneously, specific inclusion and exclusion criteria should be established at the design stage, to ensure that those with the outcome are correctly identified.
The data collection methods will depend on the exposure, outcome and study setting,
Include questionnaires and interviews, as well as medical examinations.
Routine data sources may also be used

Non-response bias
A particular problem affecting cross-sectional studies and can result in bias of the measures of outcome.
Characteristics of non-responders differ from responders.
Selection bias
The selected sample is no representative of the studied population
All factors (exposure, outcome, and confounders) are measured simultaneously. prevalence:
In analytical cross-sectional studies, the OR can be used to assess the strength of an association between a risk factor and health outcome of interest

Advantages
Quick and cheap
Able to measure prevalence for all factors under investigation
Multiple outcomes and exposures can be studied
Examine associations
Good for generating hypotheses
Disadvantages
Snapshot in time
Temporal associations not clear
Selection bias
Over-representation of cases with long duration
Underestimate of cases with short duration.
Shows association, not

1000 people were selected, among them 100 were found positive for CHD. Among the 750 who reported that they are active, 50 are CHD present
Present CHD Absent CHD
Not Active (a) 50 (b) 200 250
Active (c) 50 (d) 700 750
100 900 1000
P1= a/a+b= 50/250 = 20% prevalence of CHD among people who are not active.
P0= c/c+d = 50/750 = 6.7% prevalence of CHD among people who are active.
A hypothetical study of the effect of alcohol intake on the risk of gallstones was conducted.
 Ultrasonography of the gallbladder of 2200 study subjects identified
152
subjects with gallstones, 42 of whom listed their alcohol consumption level as "high". Of the men without gallstones, 220 listed their alcohol level as "high". Interviews were conducted at the same time as the examinations to determine the exposure level of study participants.
 What is the prevalence of gallstone among high alcohol +ve
 What is the prevalence of gallstone among high alcohol -ve
 What is the prevalence of gallstone in the studied
Gs +ve GS -ve
Alcohol +ve 42 220 262
Alcohol –ve 110 1828 1938
152 2048 2200
 P1= a/a+b= 42/262 = 19.9% prevalence of GS among people who reported +ve high alcohol consumption. P0= c/c+d = 110/1938 = 5.7% prevalence of GS among people who reported –ve high alcohol consumption.
 The total prevalence= 152/2200=6.9% OR= 42X1828/220X110= 3.2

 Case report: a careful, detailed report by one or more clinicians of the profile of a single patient.
 The individual case report can be expanded to a case series, which describes characteristics of a number of patients with a given disease.
 Uses
 Important link between clinical medicine and epidemiology
 One of the first steps in outbreak investigation
 Often useful for hypothesis generating and examining new diseases, but conclusions about etiology cannot be made.

Advantage
Inexpensive.
Data collection easy.
Short time of study.
Generates hypotheses; first step
Disadvantage
 No controls.
Patients not representative.
 Biases - patients, referral patterns, confounders.
Temporal relationship unclear.
 Lack of Generalizability.

Meta-analysis is a systematic, objective way to combine data from many studies, usually from RCTs, and arrive at a pooled estimate of treatment effectiveness and statistical significance.
Meta-analysis can also combine data from case/control and cohort studies.
The advantage to merging these data is that it increases sample size and allows for analyses that would not otherwise be possible.

They should not be confused with reviews of the literature or systematic reviews.
Two problems with meta-analysis are
publication bias (studies showing no effect or little effect are often not published and just “filed” away) and
the quality of the design of the studies from which data is pulled.
This can lead to misleading results when all the data on the subject from “published” literature are summarized.
 A comprehensive survey of a topic that takes great care to find all relevant studies of the highest level of evidence, published and unpublished, assess each study, synthesize the findings from individual studies in an unbiased, explicit and reproducible way and present a balanced and impartial summary of the findings with due consideration of any flaws in the evidence.
 In this way it can be used for the evaluation of either existing o new technologies and practices.
 It is more rigorous than a traditional literature review and attempts to reduce the influence of bias.
 In order to do this, a systematic review follows a formal process:
 Clearly formulated research question
 Published & unpublished (conferences, company reports, “file drawer reports”, etc.) literature is carefully searched for relevant research
 Identified research is assessed according to an explicit methodology
 Results of the critical assessment of the individual studies are combined
 Final results are placed in context, addressing such issues are quality of the included studies, impact of bias and the applicability of the findings