1 Clinical Study: Design and Methods

2 “Systematic investigation towards increasing the sum of knowledge” (Chambers 20th Century Dictionary) “an endeavour to discover new or collate old facts etc. by the scientific study of a subject or by a course of critical investigation.” (The Concise Oxford Dictionary) Definitions of Research

3 Where to Start? A good clinical study starts with A good clinical study starts with a good question based on good hypothesis that is based on good and comprehensive review of the available evidence from pre-clinical and clinical data a good question based on good hypothesis that is based on good and comprehensive review of the available evidence from pre-clinical and clinical data Type of design depends on the question to be answered Type of design depends on the question to be answered

4 Formulating a Research Question Focused and specific Focused and specific What is the prevalence of Hepatitis B surface Antigen in Saudi Arabia? Cross-sectional study What is the prevalence of Hepatitis B surface Antigen in Saudi Arabia? Cross-sectional study What are the risk factors for hepatitis B infection? Prospective cohort or case- control What are the risk factors for hepatitis B infection? Prospective cohort or case- control Is interferon a useful therapy for hepatitis B infection? Therapeutic clinical trial Is interferon a useful therapy for hepatitis B infection? Therapeutic clinical trial Supported by available data Supported by available data Is vancomycin better than ceftazidime against gram negative organisms? Is vancomycin better than ceftazidime against gram negative organisms? Not a replication of already established evidence Not a replication of already established evidence Is smoking associated with lung cancer? Is smoking associated with lung cancer? Ethical Ethical Answerable Answerable Methods, resources ….etc Methods, resources ….etc

5 Objectives Specific aims Specific aims Clear and detailed Clear and detailed End point(s) End point(s) Primary Primary The main answer to the research question The main answer to the research question Secondary Secondary Answer other related questions Answer other related questions

6 Study Design Your question Your question Describe Describe Analyze Analyze Your resources Your resources Retrospective Retrospective Prospective Prospective Community Community Acceptance of research Acceptance of research Observational Observational Interventional Interventional

7 Clinical Study Types Observational Studies Observational Studies Cohort (Incidence, Longitudinal) Cohort (Incidence, Longitudinal) Case-Control Case-Control Cross-Sectional (Prevalence) Cross-Sectional (Prevalence) Case Series Case Series Case Report Case Report Ecological Studies Ecological Studies Experimental Studies Experimental Studies Uncontrolled Trials Uncontrolled Trials Controlled Trials Controlled Trials

8 Level I: N of 1 randomized trial (double-blinded, cross-over) Level I (A):Systematic reviews of randomized trials Level I (B):Single randomized trial Level II (A):Systematic review of observational studies addressing patient-important outcome Level II (B):Single observational study addressing important outcome Level III:Physiologic studies Level IV:Unsystematic clinical observations (case-reports, anecdotal) Levels of Evidence Hierarchy of Strength of Evidence for Treatment Decisions JAMA 2000; 284(10):

9 Observational study  Clinical trial exposed non exposed outcome Clinical Trial observational study describe as occurring in nature allocate randomly Ethics!

10 Important issues in Study Design Validity: Truth Validity: Truth External Validity: External Validity: Can the study be generalized to the population Can the study be generalized to the population Internal Validity: Internal Validity: Results will not be due to chance, bias or confounding factors Results will not be due to chance, bias or confounding factors Symmetry Principle: Groups are similar Symmetry Principle: Groups are similar

11 Confounding: distortion of the effect of one risk factor by the presence of another Bias: Any effect from design, execution, & interpretation that shifts or influences results Confounding bias: failure to account for the effect of one or more variables that are not distributed equally Measurement bias: measurement methods differ between groups Sampling (selection) bias: design and execution errors in sampling Important issues in Study Design

Bias in studies Bias used to construct a study so that one outcome is more likely to occur than another Types: Selection Bias Measurement Bias Lifetime Bias Experimenter Expectancy Recall Bias Late look Bias Confounding Bias Design Bias Sampling Bias

The selected sample is not representative of the population Can occur if the subjects are permitted to chose whether which group to go into or The investigator purposely chooses which patient go into which group Types: Berkson Bias - A form of selection bias that causes hospital cases and controls in a case control study to be systematically different from one another because the combination of exposure to risk and occurrence of disease increases the likelihood of being admitted to the hospital. Non respondent Bias Solution: random, independent data Selection Bias

Information is gathered in a manner that distort the information Hawthrone Effect occurs when subject’s behavior is altered because they are being study Solution– A control Group Measurement Bias

Experimenter’s expectation inadvertently communicated to the subjects who then produce the desired effect(Pygmalion Effect) Solution Double Blind Studies Experimenter expectancy

Lead time Bias Gives a false estimates of survival rates Solution: life expectancy to asses benefits

Recall Bias Participants inaccurately recall events in the past Solution - Confirmation

Late look Bias Individual with severe disease are less likely to be uncovered in a survey because they will die first Solution- class disease in terms of severity

Sampling Bias Subjects are not representative of the population being studied Solution- random, independent sample

Confounding Bias The factor that is being investigated is related to other factors or of less interest Can obscure a relationship or make it seems that there is one when there is none

Design Bias Design Bias- parts of the study do not fit together to answer the question of interest common issue is no comparable groups Design Bias- parts of the study do not fit together to answer the question of interest common issue is no comparable groups Solution: Random assignment

Preventing Bias Involves the use of : Involves the use of : Blind studies Placebos Crossover Studies Randomized Studies

Blind Studies Single blind studies - only the subject does not know what treatment they are receiving Single blind studies - only the subject does not know what treatment they are receiving Double Blind Studies- neither the subject nor the evaluator knows what treatment the subject is receiving or which group received the treatment or is the control. Double Blind Studies- neither the subject nor the evaluator knows what treatment the subject is receiving or which group received the treatment or is the control. Triple Blind studies – neither the subject, the evaluator nor the analyst knows what the treatment the subject and control group receive. Triple Blind studies – neither the subject, the evaluator nor the analyst knows what the treatment the subject and control group receive.

Placebos In a blind study a patient is given a placebo(in active drug) rather than an active drug In a blind study a patient is given a placebo(in active drug) rather than an active drug Control group receive the placebo while the experimental group receive the active drug Control group receive the placebo while the experimental group receive the active drug Placebo Effect Placebo Effect

Crossover Studies Two groups Two groups One group receive the drug the other a placebo One group receive the drug the other a placebo Later the placebo group is given the drug and the group who was initially given the drug is given the placebo Later the placebo group is given the drug and the group who was initially given the drug is given the placebo Each subject act as their control Each subject act as their control

Randomization Subjects are randomly allocated into the intervention group and control group Subjects are randomly allocated into the intervention group and control group Regarded as the most scientifically rigorous study in epidemiology Regarded as the most scientifically rigorous study in epidemiology

27 Introduction Why this study is needed ? What is the purpose of this study? Was purpose known before the study? Was purpose known before the study? What has been done before and how does this study differ? What has been done before and how does this study differ? inadequacies of earlier work or next step in an overall research project inadequacies of earlier work or next step in an overall research project Does the location of the study have relevance? Does the location of the study have relevance?

28 Why doing a study? Alternative: Alternative: census: test every individual in the population census: test every individual in the population use available data, e.g. hospitals use available data, e.g. hospitals But: - data availability - data quality - cost - questions require specific type of data and circumstances

29 Types of observational studies CROSS - SECTIONAL STUDY CROSS - SECTIONAL STUDY COHORT STUDY COHORT STUDY CASE CONTROL STUDY CASE CONTROL STUDY CASE SERIES/CASE REPORTS CASE SERIES/CASE REPORTS ECOLOGICAL STUDIES ECOLOGICAL STUDIES

30 Characteristics of observational studies No control over study units No control over study units need to clearly describe study individuals need to clearly describe study individuals Can study risk factors that have serious consequences Can study risk factors that have serious consequences Study individuals in their natural environment (>> extrapolation) Study individuals in their natural environment (>> extrapolation) Possibility of confounding Possibility of confounding

31 Aims of observational studies  Evaluate the effect of a suspected risk factor (exposure) on an outcome (e.g. disease)  define ‘exposure’ and ‘disease’  Describe the impact of the risk factor on the frequency of disease in a population

32 Cross - Sectional Study

33 Cross - Sectional Study (1) Exposure and disease measured once, i.e. at the same point in time Exposure and disease measured once, i.e. at the same point in time present futurepast n exposed ? diseased ?

34 Cross - Sectional Study (2) Random sample from population Random sample from population i.e. results reflect reference population i.e. results reflect reference population Estimates the frequencies of both exposure and outcome in the population Estimates the frequencies of both exposure and outcome in the population Measuring both exposure and outcome at one point in time Measuring both exposure and outcome at one point in time Typically a survey Typically a survey

35 Cross - Sectional Study (3) Can study several exposure factors and outcomes simultaneously Can study several exposure factors and outcomes simultaneously Determines disease prevalence Determines disease prevalence Helpful in public health administration & planning Helpful in public health administration & planning Quick Quick Low cost (e.g. mail survey) Low cost (e.g. mail survey) Limitation: Limitation: Does not determine causal relationship Does not determine causal relationship Not appropriate if either exposure or outcome is rare Not appropriate if either exposure or outcome is rare

36 Cohort Studies

37 Cohort studies Follow-up studies; subjects selected on presence or absence of exposure & absence of disease at one point in time. Disease is then assessed for all subjects at another point in time. Follow-up studies; subjects selected on presence or absence of exposure & absence of disease at one point in time. Disease is then assessed for all subjects at another point in time. Typically prospective but can be retrospective, depending on temporal relationship between study initiation & occurrence of disease. Typically prospective but can be retrospective, depending on temporal relationship between study initiation & occurrence of disease.

Cohort Studies Basics Base line Exposure Exposure Development of HO Cohort: Male and Female British Physicians Exposure: Smoking

Cohort Design time Study begins here Study population free of disease Factor present Factor absent disease no disease disease no disease present future

40 Cohort Study (1) Individuals selected by exposure status and future occurrence of disease measured Individuals selected by exposure status and future occurrence of disease measured More clearly established temporal sequence between exposure & disease More clearly established temporal sequence between exposure & disease Allows direct measurement of incidence Allows direct measurement of incidence Allows establishment of Causality Allows establishment of Causality Examines multiple effects of a single exposure (nurses’ health study, OC and breast, ovarioan cancers) Examines multiple effects of a single exposure (nurses’ health study, OC and breast, ovarioan cancers)

41 Cohort studies (3) Limitations: Limitations: time consuming and expensive time consuming and expensive loss to follow-up & unavailability of data loss to follow-up & unavailability of data potential confounding factors potential confounding factors inefficient for rare diseases inefficient for rare diseases

42 Prospective Cohort Study without outcome Cohort with outcome without outcome Exposed Unexposed Time Onset of study Direction of inquiry Q: What will happen?

43 Prospective Cohort Study Appropriate for frequent disease Appropriate for frequent disease Can examine only few risk factors Can examine only few risk factors Usually expensive Usually expensive RR = ‘relative risk’ = incidence rate ratio RR = ‘relative risk’ = incidence rate ratio AR = incidence difference AR = incidence difference

Calculation of Relative Risk B D Outcome Present Absent PresentAbsent Total A + B C + D Total A C B + D A + C Relative Risk A A + B C C + D Exposure

Cohort Studies Relative Risk Relative Risk Attributable Risk Attributable Risk Number needed to Treat Number needed to Treat Number needed to Harm Number needed to Harm 45

Attributable Risk Incidence in Exposed – Incidence in Non exposed Incidence in Exposed – Incidence in Non exposed 46

Number needed to Treat/Harm Inverse of Attributable Risk in Treated patient - NNT Inverse of Attributable Risk in Treated patient - NNT Inverse of Attributable Risk in Exposed group - NNH Inverse of Attributable Risk in Exposed group - NNH 47

48 Case-Control Studies

49 Case-Control Study (1) Retrospective Retrospective Can use hospital or health register data Can use hospital or health register data First identify cases First identify cases Then identify suitable controls Then identify suitable controls Hardest part: who is suitable ?? Hardest part: who is suitable ?? Then inquire or retrieve previous exposure Then inquire or retrieve previous exposure By interview By interview By databases (e.g. hospital, health insurance) By databases (e.g. hospital, health insurance)

50 Case-Control Study (2) Diseased and non-diseased individuals are selected first Diseased and non-diseased individuals are selected first Then past exposure status is retrieved Then past exposure status is retrieved present futurepast n disease exposed ? yes no

51 Case-Control Study (3) Good for rare disease (e.g. cancer) Good for rare disease (e.g. cancer) Can study many risk factors at the same time Can study many risk factors at the same time Usually low cost Usually low cost Confounding likely Confounding likely OR (not RR !!) OR (not RR !!)

Case Control Design time Study begins here Factor present Factor absent disease no disease disease no disease Past Present

53 Case-Control Study Design Cases Controls Exposed Unexposed Exposed Unexposed Time Data collection Direction of inquiry Q: What happened?

Calculation of Odd Ratio B D Outcome Present Absent PresentAbsent Total A + B C + D Total A C B + D A + C Odd Ratio A C B D Exposure

55 Study subjects selected on basis of whether they have (case) or do not have (control) a disease Study subjects selected on basis of whether they have (case) or do not have (control) a disease Useful for disease with long latency period Useful for disease with long latency period Efficient in terms of time & costs Efficient in terms of time & costs Particularly suited for rare diseases Particularly suited for rare diseases Examines multiple exposures to a single disease Examines multiple exposures to a single disease Case-Control study (4)

56 Case-control study (5) Limitations: (1) susceptible to bias (particularly selection & recall) (2) difficulties in selection of controls (3) ascertainment of disease & exposure status (4) inefficient for rare exposures unless attributable risk is high

57 Case Selection Define source population Cases –incident/prevalent –diagnostic criteria (sensitivity + specificity) Controls –selected from same population as cases –select independent of exposure status

58 Control Selection Random selection from source population Hospital based controls: –convenient selection –controls from variety of diagnostic groups other than case diagnosis –avoid selection of diagnoses related to particular risk factors –limit number of diagnoses in individuals

59 Summary of Observational Studies Data Analysis Chi Square Odd Ratio Relative Risk

Two or more groups compared? Case Report Case Series Identify Exposure and Outcome What is determined first in the study? Exposure and outcome and determined at the same time Clinical Trial Cross-Sectional Study Cohort Study Cases Control Study Is exposure assigned by investigators? Outcome is determined first Exposure is determined first Yes No Yes