Introduction to Clinical Research Design

Introduction to Introduction to Clinical Research Clinical Research DesignDesign

Lee E. Morrow, MD, MSLee E. Morrow, MD, MSAssistant Professor of Assistant Professor of

MedicineMedicineCreighton UniversityCreighton University

Clinical Research DesignsClinical Research DesignsDescriptiveDescriptive• Describe Describe

incidence of incidence of outcomes over outcomes over timetime• Case ReportsCase Reports• Case SeriesCase Series• RegistriesRegistries• Cross SectionsCross Sections

AnalyticAnalytic• Analyze Analyze

associations associations between predictors between predictors and outcomesand outcomes• ObservationalObservational

• Cohort StudiesCohort Studies• Case-Control StudiesCase-Control Studies

• ExperimentalExperimental• Clinical TrialsClinical Trials

Descriptive StudiesDescriptive Studies• Often a first step in researchOften a first step in research• Doesn’t always have a specific Doesn’t always have a specific

hypothesis to be testedhypothesis to be tested• Causality usually cannot be determinedCausality usually cannot be determined• Examples:Examples:

• Case Reports/SeriesCase Reports/Series• RegistriesRegistries• Cross Sectional StudiesCross Sectional Studies

Case Reports/SeriesCase Reports/Series• Definition: A single/series of patients Definition: A single/series of patients

with or without a disease or exposure of with or without a disease or exposure of interest for whom data are collected in interest for whom data are collected in any fashionany fashion

• Sources: Clinics, hospitals, disease Sources: Clinics, hospitals, disease registriesregistries

• Limitations: Not randomly selected, bias Limitations: Not randomly selected, bias due to selection factors inherent in the due to selection factors inherent in the source, not representative of the source, not representative of the population from which they are selectedpopulation from which they are selected

Case Reports/SeriesCase Reports/Series• Benefits: Easy to do, useful for exploring Benefits: Easy to do, useful for exploring

relationships and/or generating relationships and/or generating hypotheseshypotheses

• Key Point: Associations seen in case Key Point: Associations seen in case series are highly likely to be biased and series are highly likely to be biased and frequently do NOT hold up in more frequently do NOT hold up in more rigorous studiesrigorous studies

Cross-Sectional StudiesCross-Sectional Studies• Definition: A study based on a sample Definition: A study based on a sample

selected at selected at one point or period in timeone point or period in time

PopulationPopulation

Risk Factor Risk Factor PresentPresentRisk Factor Risk Factor AbsentAbsent



SampleSamplePopulationPopulation




SampleSamplePopulationPopulation

No No DiseaseDisease

DiseaseDisease

DiseaseDisease



Cross-Sectional StudiesCross-Sectional Studies• If looking at a specified moment in time: If looking at a specified moment in time:

point prevalencepoint prevalence• If looking at a specified moment in time If looking at a specified moment in time

plus all new cases during the specified plus all new cases during the specified time period: time period: period prevalenceperiod prevalence

• If looking only at new cases during the If looking only at new cases during the specified time period: specified time period: incidenceincidence

Cross-Sectional StudiesCross-Sectional StudiesWhich cases are included in 7/1/02 point prevalence?Which cases are included in 7/1/02 point prevalence?Which cases are included in 7/1/02-6/30/03 period Which cases are included in 7/1/02-6/30/03 period prevalence?prevalence?Which cases are included in incidence?Which cases are included in incidence?

7/1/027/1/02 6/30/036/30/03

1122

3344

6677

8899

55

Cross-Sectional StudiesCross-Sectional Studies7/1/02 point prevalence cases: 1, 2, 87/1/02 point prevalence cases: 1, 2, 87/1/02-6/30/03 period prevalence cases: 1, 2, 3, 4, 6, 8, 97/1/02-6/30/03 period prevalence cases: 1, 2, 3, 4, 6, 8, 9incidence cases: 3, 4, 6, 9incidence cases: 3, 4, 6, 9

7/1/027/1/02 6/30/036/30/03

1122

3344

6677

8899

55

Cross-Sectional StudiesCross-Sectional StudiesAssuming N=100, calculate the 7/1/02 point prevalence.Assuming N=100, calculate the 7/1/02 point prevalence.Calculate the 7/1/02-6/30/03 period prevalence.Calculate the 7/1/02-6/30/03 period prevalence.Calculate the incidence rate.Calculate the incidence rate.

7/1/027/1/02 6/30/036/30/03

1122

3344

6677

8899

55

Cross-Sectional StudiesCross-Sectional Studies7/1/02 point prevalence: 3%7/1/02 point prevalence: 3%7/1/02-6/30/03 period prevalence: 7%7/1/02-6/30/03 period prevalence: 7%incidence rate: 4%incidence rate: 4%

7/1/027/1/02 6/30/036/30/03

1122

3344

6677

8899

55

Cross-Sectional StudiesCross-Sectional Studies• Limitations: Limitations:

• Exposure and outcome are assessed at the Exposure and outcome are assessed at the same time by the investigator (no same time by the investigator (no temporality)temporality)

• Sample selection is not based on exposure Sample selection is not based on exposure or outcomeor outcome

• Prevalence estimate is affected by duration Prevalence estimate is affected by duration of disease: disease with longer duration is of disease: disease with longer duration is more likely to be detectedmore likely to be detected

• Must consider “at risk” population onlyMust consider “at risk” population only

Cross-Sectional StudiesCross-Sectional Studies• Benefits Benefits

• EasyEasy• CheapCheap• Gives a “snap-shot” of exposure and Gives a “snap-shot” of exposure and

outcomeoutcome• Good for hypothesis generationGood for hypothesis generation

Analytic StudiesAnalytic Studies• Involve a specific hypothesis that can Involve a specific hypothesis that can

be tested using a statistical modelbe tested using a statistical model• Involve assessing exposures as a Involve assessing exposures as a

predictor of outcomespredictor of outcomes• Examples:Examples:

• Observational: Cohort Studies, Case-Control Observational: Cohort Studies, Case-Control StudiesStudies

• Experimental: Clinical TrialsExperimental: Clinical Trials

Cohort StudiesCohort Studies• Involve following a group (cohort) of Involve following a group (cohort) of

subjects over timesubjects over time• Usually analytic but may be descriptiveUsually analytic but may be descriptive• Was a treatment specifically initiated for Was a treatment specifically initiated for

evaluation?evaluation?• No: Simple Cohort StudyNo: Simple Cohort Study• Yes: Yes: Clinical TrialClinical Trial

• RandomizedRandomized• Non-RandomizedNon-Randomized

Cohort StudiesCohort Studies• Prospective Cohort StudiesProspective Cohort Studies

• Investigator defines sample and predictor Investigator defines sample and predictor variables before any outcomes have variables before any outcomes have occurredoccurred

• Retrospective Cohort StudiesRetrospective Cohort Studies• Investigator defines sample and collects Investigator defines sample and collects

information about predictor variables after information about predictor variables after the outcomes have occurredthe outcomes have occurred

Prospective Cohort StudiesProspective Cohort Studies


The PresentThe Present

PopulationPopulation

Is a given Risk Factor associated with a given Disease?Is a given Risk Factor associated with a given Disease?



The PresentThe Present

PopulationPopulation SampleSample





DiseaseDisease

DiseaseDisease


The PresentThe Present The FutureThe Future



Retrospective Cohort Retrospective Cohort StudiesStudies


DiseaseDisease

DiseaseDisease


The The PresentPresent





DiseaseDisease

DiseaseDisease


The PastThe Past The The PresentPresent



Cohort Studies in GeneralCohort Studies in General• StrengthsStrengths

• Powerful strategy for directly measuring the Powerful strategy for directly measuring the incidence of a diseaseincidence of a disease

• Can examine multiple outcomes and Can examine multiple outcomes and multiple exposuresmultiple exposures

• Easier to establish temporal relationship: Easier to establish temporal relationship: improves inference for causalityimproves inference for causality

Cohort Studies in GeneralCohort Studies in General• WeaknessesWeaknesses

• Attrition of the sampleAttrition of the sample• Level of exposure may change over timeLevel of exposure may change over time• Inability to identify presence of confounders Inability to identify presence of confounders

and effect modifiersand effect modifiers• Susceptible to follow-up bias: there may be a Susceptible to follow-up bias: there may be a

difference in the exposure-disease relationship difference in the exposure-disease relationship for those who follow-up and those who do notfor those who follow-up and those who do not

• Cost and feasibility vs. representativeness: Cost and feasibility vs. representativeness: general population sample vs. restricted cohort general population sample vs. restricted cohort samplesample

Prospective Cohort StudiesProspective Cohort Studies• StrengthsStrengths

• Allows opportunity for complete and Allows opportunity for complete and accurate measurement of risk factorsaccurate measurement of risk factors

• Uniquely valuable for studying the Uniquely valuable for studying the antecedents of fatal diseasesantecedents of fatal diseases

• End-point unknown: can take a long time for End-point unknown: can take a long time for sufficient number of cases to developsufficient number of cases to develop

• Observer biasObserver bias• WeaknessesWeaknesses

• Expensive and inefficient for rare diseasesExpensive and inefficient for rare diseases• Observer biasObserver bias


• StrengthsStrengths• Much less costly and time consumingMuch less costly and time consuming• Observer bias Observer bias

• WeaknessesWeaknesses• Less control over the nature and quality of Less control over the nature and quality of

predictor variable data collectedpredictor variable data collected• Incomplete data setsIncomplete data sets• Observer bias, recall biasObserver bias, recall bias

Risk Ratios in Cohort Risk Ratios in Cohort StudiesStudies

• The Risk Ratio (RR) is the ratio of the The Risk Ratio (RR) is the ratio of the incidence of disease in exposed persons incidence of disease in exposed persons to the incidence of disease in non-to the incidence of disease in non-exposed personsexposed persons

RR =RR = Cumulative Incidence in ExposedCumulative Incidence in ExposedCumulative Incidence in Non-Cumulative Incidence in Non-

ExposedExposed


• RR calculation requires RR calculation requires incidenceincidence data data• Used in cohort and intervention studiesUsed in cohort and intervention studies• Not used in Case-ControlNot used in Case-Control

RR = RR = a/a/(a+b)(a+b)c/(c+d)c/(c+d)

aa bb

cc dd

DiseasedDiseased++ --

Expo

sed

Expo

sed ++

--


• Is a measure of the strength of Is a measure of the strength of association between exposure and association between exposure and outcome: does not imply causality…outcome: does not imply causality…

Case-Control StudiesCase-Control Studies• Compares people with disease (cases) Compares people with disease (cases)

to people without disease (controls) to people without disease (controls) with respect to history of exposurewith respect to history of exposure

• If exposure is different between cases If exposure is different between cases and controls, an association exists and controls, an association exists between exposure and diseasebetween exposure and disease

• Cases must represent the population of Cases must represent the population of all cases while controls must represent all cases while controls must represent the population of all non-diseased the population of all non-diseased

Case-Control StudiesCase-Control Studies

Population withPopulation withDiseaseDisease

Population Population withoutwithoutDiseaseDisease






Risk Factor Risk Factor PresentPresent

Risk Factor Risk Factor AbsentAbsent







Select CasesSelect Cases

Select ControlsSelect Controls







The PastThe Past D+/RF+ D+/RF+ D+/RF-D+/RF-

D-/RF+ D-/RF-D-/RF+ D-/RF-

Case-Control StudiesCase-Control Studies• StrengthsStrengths

• Shorter study period is possibleShorter study period is possible• Rare diseases are more easily studiedRare diseases are more easily studied• Less expensiveLess expensive• Multiple risk factors may be studiedMultiple risk factors may be studied• Particularly useful for studying new diseases Particularly useful for studying new diseases

about which little is knownabout which little is known

Case-Control StudiesCase-Control Studies• WeaknessesWeaknesses

• Choice of appropriate controls is usually Choice of appropriate controls is usually very difficult (selection bias)very difficult (selection bias)

• Cases and controls do not usually come Cases and controls do not usually come from the same population (selection bias)from the same population (selection bias)

• May be difficult to assess whether exposure May be difficult to assess whether exposure preceded disease (recall bias)preceded disease (recall bias)

• Incidence rates cannot be calculated Incidence rates cannot be calculated directlydirectly

Odds Ratios in Case-Odds Ratios in Case-Control StudiesControl Studies

• The Odds Ratio (OR) provides an The Odds Ratio (OR) provides an estimate of the Risk Ratio (RR) for Case-estimate of the Risk Ratio (RR) for Case-Control studiesControl studies

• OR is a good estimate of the RR if the OR is a good estimate of the RR if the disease is “rare” (incidence <10% per disease is “rare” (incidence <10% per year in the population)year in the population)

• Is a measure of the strength of Is a measure of the strength of association between exposure and association between exposure and outcome: does not imply causality…outcome: does not imply causality…

Nested Case-Control Nested Case-Control StudiesStudies

• Select disease cases from within a Select disease cases from within a cohort studycohort study

• Controls are selected from non-diseased Controls are selected from non-diseased cases within the same cohort, within the cases within the same cohort, within the same time period as the cases developsame time period as the cases develop

• If controls are randomly selected from If controls are randomly selected from within the cohort (i.e.: includes diseased within the cohort (i.e.: includes diseased subjects in the case group and the subjects in the case group and the control group) it is a Case-Cohort Studycontrol group) it is a Case-Cohort Study

A Few Words About A Few Words About ControlsControls

• The most difficult aspect of Case-Control The most difficult aspect of Case-Control Studies is selecting appropriate controlsStudies is selecting appropriate controls

• Matching is often used to eliminate the Matching is often used to eliminate the effect of potential confounderseffect of potential confounders• Technically speaking, matching reduces the Technically speaking, matching reduces the

variance of the OR!variance of the OR!• Matching is difficult to do correctly and Matching is difficult to do correctly and

may paradoxically worsen analysis may paradoxically worsen analysis problems if done incorrectlyproblems if done incorrectly

• Impossible to match for unknown Impossible to match for unknown confoundersconfounders

Clinical TrialsClinical Trials• Definition: A clinical trial is a Definition: A clinical trial is a scientific scientific

experimentexperiment involving involving human subjectshuman subjects which is designed to which is designed to evaluateevaluate the the effects of effects of intervention(s)intervention(s) against a against a particular disease in order to particular disease in order to elucidate elucidate the most appropriate care for future the most appropriate care for future subjectssubjects

Clinical TrialsClinical Trials• Controlled* or UncontrolledControlled* or Uncontrolled

• Is there a concurrent comparison group?Is there a concurrent comparison group?• Randomized* or NonrandomizedRandomized* or Nonrandomized

• Are subjects randomly allocated to the Are subjects randomly allocated to the control and experimental groups?control and experimental groups?

• Parallel Group or CrossoverParallel Group or Crossover• Parallel group implies each subject receives Parallel group implies each subject receives

only one of the interventionsonly one of the interventions• Crossover implies each subject receives Crossover implies each subject receives

successively each of the interventionssuccessively each of the interventions*Hence the terminology RCT*Hence the terminology RCT

Clinical Trials: Clinical Trials: RandomizationRandomization

• Participants are randomly assigned to Participants are randomly assigned to “Exposure” or “No Exposure”“Exposure” or “No Exposure”

• Randomization refers to assigning Randomization refers to assigning subject to an intervention arm without subject to an intervention arm without regard for baseline characteristicsregard for baseline characteristics

• Goal of randomization is to equalize all Goal of randomization is to equalize all other exposures that may confound or other exposures that may confound or bias the association between Treatment bias the association between Treatment and Outcomeand Outcome

Clinical Trials: BlindingClinical Trials: Blinding• Single Blinding: examiners do not know Single Blinding: examiners do not know

treatment assignmenttreatment assignment• Double Blinding: examiners and Double Blinding: examiners and

subjects do not know treatment subjects do not know treatment assignmentassignment

• Triple Blinding: examiners, subjects, Triple Blinding: examiners, subjects, and statisticians do not know treatment and statisticians do not know treatment assignmentsassignments

• Blinding is not always possible…Blinding is not always possible…

Clinical TrialsClinical Trials• AdvantagesAdvantages

• Minimizes confounding and bias through Minimizes confounding and bias through randomizationrandomization

• Allows clear assessment of temporal Allows clear assessment of temporal associationassociation

• Permits a test of causality between Permits a test of causality between exposure and diseaseexposure and disease

Clinical TrialsClinical Trials• DisadvantagesDisadvantages

• Ethical considerations of treatment or with-Ethical considerations of treatment or with-holding treatmentholding treatment

• Harms (drug side effects, emotional Harms (drug side effects, emotional distress) may outweigh benefitsdistress) may outweigh benefits

• Expensive and time-consumingExpensive and time-consuming• Loss to follow upLoss to follow up• Non-adherence to group assignmentNon-adherence to group assignment• Possible early terminationPossible early termination• Cannot always randomize an exposureCannot always randomize an exposure

Quasi-ExperimentationQuasi-Experimentation• This is essentially a clinical trial without This is essentially a clinical trial without

randomizationrandomization• Not possible to randomize: patients being Not possible to randomize: patients being

enrolled in a rare disease trial at a site which enrolled in a rare disease trial at a site which does not have access to a given interventiondoes not have access to a given intervention

• Not ethical to randomize: patients with Not ethical to randomize: patients with cancer who have already failed the chemo in cancer who have already failed the chemo in one arm of a trial cannot ethically be one arm of a trial cannot ethically be randomized to that armrandomized to that arm

• Uses statistical deductive processes to Uses statistical deductive processes to rule out threats to plausibilityrule out threats to plausibility

• Causal inference is less strongCausal inference is less strong

Factorial DesignsFactorial Designs• This is essentially an This is essentially an

attempt to evaluate multiple attempt to evaluate multiple interventions concurrentlyinterventions concurrently

• Given costs and Given costs and inconvenience of recruiting, inconvenience of recruiting, this is particularly appealingthis is particularly appealing

• Not a valid model if Not a valid model if interaction, adds complexity, interaction, adds complexity, potential for polypharmacy, potential for polypharmacy, reviewer skepticismreviewer skepticism

aa bb

cc dd

InterventionInterventionXX --

Inte

rven

tion

Inte

rven

tion

YY

--

CellCell InterventionInterventionaa X + YX + Ybb Y + PlaceboY + Placebocc X + PlaceboX + Placebodd PlaceboPlacebo

Example 1: Design Type?Example 1: Design Type?

• Investigators obtained lists of RNs age Investigators obtained lists of RNs age 25-42 in the 11 most populous U.S. 25-42 in the 11 most populous U.S. statesstates

• They mailed baseline questionnaires They mailed baseline questionnaires about diet and other risk factorsabout diet and other risk factors

• Follow-up questionnaires were sent Follow-up questionnaires were sent every 2 years for 20 years assessing every 2 years for 20 years assessing additional risk factors and the additional risk factors and the development of disease outcomesdevelopment of disease outcomes

Example 1: Nurses’ Health Example 1: Nurses’ Health StudyStudy

• Prospective Cohort StudyProspective Cohort Study• Assembled a cohortAssembled a cohort• Assessed baseline risk factorsAssessed baseline risk factors• In the future assessed disease outcomesIn the future assessed disease outcomes

• Repeated Cross Sectional StudyRepeated Cross Sectional Study• Described changes over time in Described changes over time in

characteristics of the same study populationcharacteristics of the same study population


• Investigators reported a 12-year old boy Investigators reported a 12-year old boy with adrenomyeloneuropathy with adrenomyeloneuropathy

• Disease progression was markedly Disease progression was markedly attenuated by treatment with a attenuated by treatment with a combination of oleic and erucic acidscombination of oleic and erucic acids

Example 2: Lorenzo’s OilExample 2: Lorenzo’s Oil

• Case Report Case Report • A single patientA single patient• DescriptiveDescriptive• No specific hypothesis being testedNo specific hypothesis being tested• Often not representative of the population Often not representative of the population

at large…at large…


• Investigators assembled 23 patients Investigators assembled 23 patients with adrenomyeloneuropathy from a with adrenomyeloneuropathy from a national data basenational data base

• Randomized to two-years of treatment Randomized to two-years of treatment with oleic and erucic acids vs. placebowith oleic and erucic acids vs. placebo

• No statistically significant difference in No statistically significant difference in disease progression, survival, etc.disease progression, survival, etc.

Example 3: Lorenzo’s Oil IIExample 3: Lorenzo’s Oil II

• Randomized, Placebo Controlled Clinical Randomized, Placebo Controlled Clinical TrialTrial

• Prospective Cohort with an InterventionProspective Cohort with an Intervention• Cohort of subjects selected based on Cohort of subjects selected based on

presence of disease of interestpresence of disease of interest• Followed prospectively over timeFollowed prospectively over time• A treatment was specifically initiated for A treatment was specifically initiated for

evaluationevaluation• Treatment was allocated randomlyTreatment was allocated randomly• Treatment was compared to placeboTreatment was compared to placebo

Example 4: Design Type?Example 4: Design Type?• Investigators were interested in Investigators were interested in

determining the prevalence of various determining the prevalence of various pathology subtypes of inoperable lung pathology subtypes of inoperable lung cancercancer

• Through an institutional registry identified Through an institutional registry identified all patients diagnosed with a new lung all patients diagnosed with a new lung cancer in the prior year (476 patients)cancer in the prior year (476 patients)

• Found that 38% were epidermoid, 28% Found that 38% were epidermoid, 28% were small cell, 18% were adenocarcinoma, were small cell, 18% were adenocarcinoma, 13% were large cell, and 3% were other 13% were large cell, and 3% were other typestypes

Example 4Example 4

• Cross-Sectional StudyCross-Sectional Study• A “snapshot” in timeA “snapshot” in time• Subjects are included based on the Subjects are included based on the

designated point/period in time of interestdesignated point/period in time of interest• Purely descriptivePurely descriptive

Example 5: Design Type?Example 5: Design Type?• Investigators recorded the Investigators recorded the

smoking histories of 1357 men smoking histories of 1357 men with and 1357 age-matched with and 1357 age-matched men without lung cancermen without lung cancer

• Risk of lung cancer is Risk of lung cancer is estimated to be 3.4 times estimated to be 3.4 times greater for the smokers than greater for the smokers than for the non-smokersfor the non-smokers

• Doesn’t imply causality: Doesn’t imply causality: replace “smoked” with replace “smoked” with “carried lighter”“carried lighter”

857857 457457

500500 900900

Lung CancerLung Cancer++ --

Smok

edSm

oked ++

--

Example 5Example 5

• Case-Control StudyCase-Control Study• Investigator selects people with disease Investigator selects people with disease

(cases)(cases)• Investigator selects people without disease Investigator selects people without disease

(controls)(controls)• Matching is often used is case-control studiesMatching is often used is case-control studies• The cases and controls are then compared The cases and controls are then compared

with respect to a history of exposurewith respect to a history of exposure


• Investigators followed 40,000 British MDs Investigators followed 40,000 British MDs for 10 yearsfor 10 years

• Stratified by the number of cigarettes Stratified by the number of cigarettes smoked each day at the start of the smoked each day at the start of the studystudy

• Assessed annual death rate from lung Assessed annual death rate from lung cancercancer

• Found that the risk of death from lung Found that the risk of death from lung cancer was 32 times greater for heavy cancer was 32 times greater for heavy smokers as for non-smokerssmokers as for non-smokers

Example 6: British Physician Example 6: British Physician StudyStudy

• Prospective Cohort StudyProspective Cohort Study• Investigator selects sample (cohort) and Investigator selects sample (cohort) and

predictor variables before any outcomes predictor variables before any outcomes have occurredhave occurred

• The sample is then followed over timeThe sample is then followed over time

Example 7: Design Type?Example 7: Design Type?• Goal was to describe the natural history of Goal was to describe the natural history of

thoracic aortic aneurysms and risk factors thoracic aortic aneurysms and risk factors for rupturefor rupture

• Investigators identified 133 patients Investigators identified 133 patients diagnosed with aortic aneurysmsdiagnosed with aortic aneurysms

• Reviewed records to collect data on Reviewed records to collect data on gender, age, size of aneurysm, risk factors gender, age, size of aneurysm, risk factors for CV disease, rupture of aneurysms, and for CV disease, rupture of aneurysms, and surgical repair of aneurysmssurgical repair of aneurysms

• 31% of aneurysms >6 cm ruptured, 0% <4 31% of aneurysms >6 cm ruptured, 0% <4 cm rupturedcm ruptured

Example 7Example 7

• Retrospective Cohort StudyRetrospective Cohort Study• Identify a cohort based on past dataIdentify a cohort based on past data• Collect data on predictors from past dataCollect data on predictors from past data• Collect data on outcomes from past and/or Collect data on outcomes from past and/or

present datapresent data

Introduction to Clinical Research Design

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