Clinical Research Design and Conduction Study Design M Mohsen Ibrahim, MD Cardiac Department Cairo University
Algorithm for classification of types of clinical research Grimes DA and Schulz KF. Lancet 2002
Type of Study Descriptive Looking at individual variables one at a time Analytic Analyzing the relationships among two or more variables in order to predict outcomes Predictor Variable Outcome Variable Confounding Variable
Classification of Study Designs Observational Studies Case-series Case-control Cross-sectional Cohort / Longitudinal Retrospective Prospective Experimental Studies Controlled trials No controls Diagnostic Test
Case-Series Studies Descriptive account of interesting ti characteristics observed in a group of patients Does not include control subjects (without the disease described) Generally not planned studies Do not involve any research hypothesis Descriptive role as a precursor to other studies
Case-Series Studies Between October 1980 and May 1981, 5 cases of Pneumocystis carinii pneumonia were reported among, previously healthy, homosexual men in Los Angeles This type of pneumonia had previously occurred only in older cancer pts whose immune system was suppressed In early 1981, an unprecedented number of cases of Kaposi s sarcoma were diagnosed in young homosexual men This malignancy had been seen almost exclusively in the elderly This suggested that these individuals were actually suffering from previously unknown disease As a result of these case series the CDC immediately initiated iti t a surveillance program and developed d diagnostic criteria for what appeared to be a NEW DISEASE (AIDS). This program quickly identified that homosexual men were at high risk of developing this syndrome.
Structure Design Case-Control Studies Identify groups of subjects with (cases) and without the disease (controls) Find differences in predictor variables that may explain why cases got the disease and the controls did not Select a sample from a population of people with the disease (cases) Select a sample form a population that is free of the disease (controls) Measure predictor variables (risk factors)
Case-control design THE PAST OR PRESENT THE PRESENT Risk factor present Risk factor absent Disease Sample of case Population with disease (cases) Risk Risk Mach larger factor No disease absent factor present Sample of controls Mach larger population without disease (controls)
Indications Case-Control Studies Investigate t causes of disease Identification of risk factors Need to examine a large number of predictor variables Best option to study rare diseases or those with long latent periods between exposure and disease Advantages Relatively quick to conduct Relatively inexpensive Requires comparatively few subjects - relatively small No risks to subjects Yields odds ratio
Case-Control Studies Disadvantages No Incidence or prevalence of disease No Sequence of events Only one outcome can be studied d Potential sampling bias Potential measurement bias
Bias Selection bias Sampling bias Study sample is not representative of the target population Observation bias Measurement Bias Systematic error in the measurement of information inaccurate or incomplete data, e.g. tendency to underestimate BP in pts receiving trt
Cross-Sectional Studies Select a sample from the population Measure predictor and outcome variables All the variables are measured at a single point in time Provides information about the prevalence : proportion p of population who have the disease or risk factor at one point in time Can reveal cross-sectional associations of interest Can be included as the first step in a cohort study or experiment. The results define the demographic and clinical characteristics of the study group at baseline
Cohort ( Longitudinal ) Studies Select a sample from the population Measure predictor variables (risk factors) Follow-up the cohort Measure outcome variables (disease) Describe the incidence of the outcomes ( such as death, MI, stroke, HF, etc.) Comparing the incidence of outcome in those with the predictor of interest ( such as smoking, high BP, sedentary lifestyle, obesity, etc.) with the incidence of those who do not have the predictor or have a different level l of the predictor
Cohort studies General design Start with population free of disease (of interest) Measure characteristics at baseline Particularly exposures of interest Follow them for a period of time Measure occurrence of disease Analysis occurrence of disease in persons who had/did not have exposure of interest
Schematic diagram of cohort study design Characteristics at baseline. Exposure of interest Yes, Experimental subjects Cohort selected for study (population free of disease) No, Unexposed or controls With outcome Without outcome With outcome Without outcome Onset of study Time Question: what will happed? Direction of inquiry
Prospective Cohort Studies Advantages of Cohort Studies Provides information about: Rates of progression and natural history of the disease Define the incidence and potential causes of a condition More control over selection of subjects More control over measurements - allows for thorough h quality control in measurement of study variables Can study several outcomes
Cohort Studies Disadvantages of Prospective Cohort Studies Large number of subjects are required Long duration for follow-up Relatively expensive to conduct Maintaining follow-up is difficult Cannot be used for the study of rare disease Associations found can sometimes be misleading due to the effects of confounding variables
Classification of Study Designs Observational Studies Case-series Case-control Cross-sectional Cohort / Longitudinal Experimental Studies Controlled trials No controls Diagnostic Test
Experiments Clinical Trials The purpose is to draw conclusions about a particular procedure or treatment
Experiments Clinical Trials Steps Select a sample from the population Measure baseline variables Randomize Apply interventions ( one should be a blinded placebo, if possible) Follow-up the cohorts Measure outcome variables (blindly if possible) Analyzing the results
Experiments Clinical Trials Controlled trials Experimental drug or procedure is compared with another drug or procedure, sometimes a placebo or previously accepted trt Uncontrolled trials Treatment is not compared with another trt More likely to be used when the comparison involves a procedure than when it involves a drug
Clinical Trials Controlled trials Parallel or concurrent controls Randomized Nonrandomized Sequential controls: same group of subjects for both experimental and control options Self-controlled Crossover
Randomized Clinical Trials General Design Pick an intervention usually a form of treatment You can only pick one Find a group of patients that agree to participate Have to be representative of condition Give the new treatment to some Some get the old (or no) treatment Do this randomly Follow all to see outcomes
Schematic diagram of randomized clinical trial design Experimental subjects Subjects meeting entry criteria With outcome Without outcome With outcome controls Without outcome Onset of study Intervention Time
The randomized blinded trial (RBT), in this case of the efficacy of a treatment in preventing disease The Present The Future Randomized Treatment # 1 Disease No disease Population Sample Placebo Disease No disease
An RBT preceded by a run-in period to test compliance The Present The Future Treatment Disease No disease Population Sample Treatment Randomized Placebo No Disease disease
A factorial design RBT, providing two studies for the price of one The Present The Future Drug A & Drug B Disease No disease Population Sample Drug A & Placebo B Randomized Placebo A & Drug B Placebos A &B Disease No disease Disease No disease Disease No disease
Diagnostic Tests Determines the usefulness of a test in the diagnosis of a disease Predictor variable : the test result Outcome variable : the disease The investigator must determine the appropriate cutoff point for calling a result positive
Sensitivity Diagnostic Tests Proportion of pts with the disease who have a positive test Specificity Proportion of pts without the disease who have a negative test Biases : Sampling Measurement Reporting
Summary Research question - Characteristics of a good research question. Study design- Classification a. Observational: Case-series, Case-control, Crosssectional, Cohort. b. Experimental (intervention): - Controlled - No controls. a. Diagnostic test.
Summary Observational Studies You gather the data Prevalence surveys Easy to design, Moderately time consuming and expensive to conduct Case-control hard to design, Quick and easy to conduct Cohort studies moderately hard to design. Very time-consuming and expensive to conduct