Study Designs:Study Designs: Overview, analytic Overview, analytic

techniques and techniques and measures of measures of

association/effectassociation/effectLarry Holmes, Jr.,Larry Holmes, Jr.,Jobayer HossainJobayer Hossain

Research Statistics Lecture SeriesResearch Statistics Lecture SeriesNemours, DE - October, 2008Nemours, DE - October, 2008

Research STATS

Lecture 2

What do you see? Error!!! Bias!!!What do you see? Error!!! Bias!!!

Lecture ObjectivesLecture Objectives

At the end of this presentation At the end of this presentation participants will be expected to:participants will be expected to:– Identify and describe the types of Identify and describe the types of

designs used to conduct clinical studies designs used to conduct clinical studies – Understand the selection of study Understand the selection of study

subjects or participants in researchsubjects or participants in research– Identify the measure of association or Identify the measure of association or

effect effect – Estimate relative risk and odds ratio from Estimate relative risk and odds ratio from

cohort and case-control studies cohort and case-control studies respectivelyrespectively

Why Design Strategies?Why Design Strategies?Inappropriate study designs generate Inappropriate study designs generate

validity issues that cannot be corrected validity issues that cannot be corrected by statistics, however sophisticated the by statistics, however sophisticated the

modelmodel we usewe use

““No intelligent person would underestimate No intelligent person would underestimate the importance of mathematics in science the importance of mathematics in science

or question the necessity for its or question the necessity for its correctness, but it cannot bring truth out of correctness, but it cannot bring truth out of error. If it is applied to truth it will produce error. If it is applied to truth it will produce

truth, and if it is applied to error it will truth, and if it is applied to error it will almost certainly produce error” – Dingle H, almost certainly produce error” – Dingle H,

19581958

Design or Sampling?Design or Sampling?

Research Feasibilities: Health Care Outcome Approaches

Patient

Treatment/Diagnostic

Health Care Provider

• prognostic factors

• knowledge/interest learning about cancer

• coping strategies

• quality of life

• medical specialty

• medical coverage/insurance

• access to clinical trials

• support group availability

• treatment recommendation

• treatment given

• appropriateness of treatment

• pain/symptom management

Outcome Measures

• survival

• recurrence

• new disease

• treatment complications

• health related quality of life

• disease-specific impairments

• satisfaction with care

• financial & family burden

Management

Study Conceptualization: FrameworkStudy Conceptualization: Framework

Theory/

Knowledge/

Problems

Conceptual

Hypotheses

Synthesis & Hunches

Study Design

Operational

Hypotheses

Observations/

Data

Empirical

Findings

Conclusions and

Interpretations

Data Analysis

Inferences Re Operational Ho

Inferences Re Conceptual Ho

Data Collection

Research conceptualization:Research conceptualization: Schematic representation Schematic representation of the natural history of diseaseof the natural history of disease

STAGE OF SUSCEPTIBILTY STAGE OF SUSCEPTIBILTY PRE-PRE- CLINICALCLINICAL DISABILITYDISABILITYDISEASEDISEASE SYMPTO-SYMPTO- DISEASE DISEASE OR RECOVERYOR RECOVERY

MATICMATICTISSUE TISSUE Resolution orResolution orCHANGESCHANGES Pre-PathogenesisPre-Pathogenesis Pathogenesis Pathogenesis SequelaeSequelaeLEVEL OFLEVEL OF PREVENTIONPREVENTION PrimaryPrimary SecondarySecondary Tertiary Tertiary MODES OFMODES OF Health PromotionHealth Promotion Detection Detection Treatment and Treatment and IINTERVENTION NTERVENTION Specific Specific EarlyEarly Rehabilitation Rehabilitation

ProtectionProtection DiagnosisDiagnosis Limitation ofLimitation ofPromptPrompt DisabilityDisabilityTreatmentTreatment

CAB

E

D

Outcome Death

Chronicity

Residual Disability

Inapparent or Subclinical

Clinical Disease

Clinical Horizon

Research/Study Design

Descriptive To: Describe an experience, programs, treatment, unusual observation

AnalyticExamine etiology, efficacy

ObservationalAssociation of cause and effectComparison between 2 treatments

Experimental?Evaluate the efficacy of a therapeutic , or other interventions

Examples:1) Case Reports 2) Case series3) Ecological study

Examples:

1) Cross-sectional2) Case-control3) Cohort

Examples:

1) Clinical Trial2) Community trial

Meta-analysis?Combination of studies

Ecological Study DesignEcological Study Design

The strategy is based on determining whether The strategy is based on determining whether those ecological units with a high frequency of those ecological units with a high frequency of exposure also tend to be the groups with a high exposure also tend to be the groups with a high frequency of health outcome occurrence.frequency of health outcome occurrence.

Measure group rates of the health outcome and Measure group rates of the health outcome and exposure prevalence for the same population exposure prevalence for the same population group, but not necessarily using the same source group, but not necessarily using the same source of data.of data.

Types of comparisons:Types of comparisons:– Geographical or group comparisons, e.g., Geographical or group comparisons, e.g.,

countries or administrative units.countries or administrative units.– Temporal comparisonsTemporal comparisons– Combines geographic and temporal Combines geographic and temporal

comparisonscomparisons– Time-series studies. Time-series studies.

Cross-Sectional Study Cross-Sectional Study Cross-sectional studies typically conducting a medical survey in a Cross-sectional studies typically conducting a medical survey in a community or defined population – orthopedic hospital. Key steps in community or defined population – orthopedic hospital. Key steps in conducting a cross-sectional medical survey are:conducting a cross-sectional medical survey are:

– To identify the base population To identify the base population – To choose a sampling design and sampling frame for selecting the To choose a sampling design and sampling frame for selecting the

study participantsstudy participants– To measure exposure (spine fusion) and health outcome status To measure exposure (spine fusion) and health outcome status

(post-operative pancreatitis) on the study subjects.(post-operative pancreatitis) on the study subjects.

A critical aspect of conducting a medical surveys is the logistical plans for A critical aspect of conducting a medical surveys is the logistical plans for examining the subjects and obtaining and processing any biological examining the subjects and obtaining and processing any biological specimens. specimens.

Cross-sectional studies may also be based on existing records. For Cross-sectional studies may also be based on existing records. For example, a study using data from Fracture Registry to evaluate the example, a study using data from Fracture Registry to evaluate the association between osteopena or ontogenesis imperfecta and repeated association between osteopena or ontogenesis imperfecta and repeated fractures fractures

Sampled or surveyed population

Exposure – risk present (eg. Developmental motor delay) – (n?)

Disease – TLK progression (n?)

Non-exposure – risk absent (eg. No developmental motor delay) – (n?)

Disease – thoraco lumbar kyphosis (TLK) progression (n1 ?)

Non-disease (n2?)

Non-disease – (n?)

Prevalence (PE) – n1/(n1 + n2)

Prevalence (PU) – n1/(n1 + n2)

Relative prevalence – PE/PU - Using 2x2 table a/(a+b) / c(c+d). Prevalence odds ratio – ad/bc

Cross-sectional design

Measuring Association in a Cross-Sectional Measuring Association in a Cross-Sectional StudyStudy

Simplest case is to have a dichotomous Simplest case is to have a dichotomous outcome and dichotomous predictor outcome and dichotomous predictor variablevariable

Everyone in the sample is classified as Everyone in the sample is classified as diseased or not and having the risk diseased or not and having the risk factor or not, making a 2 x 2 tablefactor or not, making a 2 x 2 table

The proportions with disease are The proportions with disease are compared among those with and without compared among those with and without the risk factorthe risk factor

2 x 2 table for association of disease and exposureDisease

Yes NoE

xpos

ure

Yes

No

a b

c d

a + b

c + d

a + c b + d N = a+b+c+d

Prevalence ratio of disease in exposed and unexposedDisease

Yes No

Exp

osur

e

Yes

No

a b

c d

a + b

c + d

c

a

PR =

Case-ControlCase-Control StudyStudy

Is a study that starts with the identification of Is a study that starts with the identification of persons with the outcome of interest and a persons with the outcome of interest and a suitable control group of persons without the suitable control group of persons without the outcome. outcome.

The relationship of an exposure to the outcome is The relationship of an exposure to the outcome is examined by comparing those with and without examined by comparing those with and without the outcome with regard to how frequently the the outcome with regard to how frequently the exposure is present, or if quantitative, the levels of exposure is present, or if quantitative, the levels of exposure in each of the groupsexposure in each of the groups

Syn: Case-referent Study; Retrospective Study; Syn: Case-referent Study; Retrospective Study;

What is a case-control study?What is a case-control study?

Case-control study is a method of Case-control study is a method of

sampling a population in which cases sampling a population in which cases

of disease are identified and enrolled, of disease are identified and enrolled,

and a sample (controls) of the and a sample (controls) of the

population that produced the cases is population that produced the cases is

identified and enrolled. identified and enrolled.

Exposures are determined for Exposures are determined for

individuals in each groupindividuals in each group. .

What is a case-control study?What is a case-control study?(Cont’d)(Cont’d)

Case-control study has two groups (case Case-control study has two groups (case group and control group): one group has the group and control group): one group has the disease of interest (cases) and a comparable disease of interest (cases) and a comparable group is free from the disease (controls).group is free from the disease (controls).

The case-control study identifies possible The case-control study identifies possible causes of disease by finding out how the two causes of disease by finding out how the two groups differ with respect to exposure to the groups differ with respect to exposure to the study factor of interest and other factors. study factor of interest and other factors.

Whatever selection factors in the referral system affected admissions of cases to a certain hospital would also affect the

admission of hospital controls.

Characteristics of the Characteristics of the Case-Control StudyCase-Control Study

A single point of observation.A single point of observation.

Defined by presence or absence of the Defined by presence or absence of the outcome.outcome.

Exposure is determined Exposure is determined retrospectively.retrospectively.

Does not directly provide incidence Does not directly provide incidence data.data.

Design of a Case-Control StudyDesign of a Case-Control Study

Hallmark of the case-control study is Hallmark of the case-control study is that it begins with people with the that it begins with people with the disease (case) and compares them to disease (case) and compares them to people without the disease (control).people without the disease (control).

This is in contrast to the design of a This is in contrast to the design of a cohort study cohort study

Design of a case-control study

Design of a case-control study. A, Starting with cases and controls.

Design of a case-control study. B, Measuring exposure in both groups.

Design of a case-control study. C, Expected findings if the exposure is associated with disease.

Design of Design of case-control studiescase-control studies

   First SelectFirst Select

   Cases (With Cases (With Disease)Disease)

Controls (Without Controls (Without Disease)Disease)

Then Measure Past ExposureThen Measure Past Exposure

    Were exposedWere exposed aa bb

    Were not exposedWere not exposed cc dd

    TotalTotal aa + + cc bb + + dd

    Proportions exposedProportions exposed a/(a+c)a/(a+c) b/(b+d)b/(b+d)

Odds Ratios in Odds Ratios in Case-Control Study Case-Control Study

Odds of an event is defined as the Odds of an event is defined as the ratio of the number of ways the ratio of the number of ways the event can occur (P) to the number event can occur (P) to the number of ways the event cannot occur (1-of ways the event cannot occur (1-P). P).

Odds= _Odds= _P__ P__

1 - P1 - PIf probability of winning n= 60%If probability of winning n= 60%

Then, odds of winning = 60%/(1-60%) Then, odds of winning = 60%/(1-60%)

= 60%/40% = 1.5. = 60%/40% = 1.5.

Odds ratio in a cohort study

Odds ratio in a case-control study.

Odds Ratio From a Case-Control StudyOdds Ratio From a Case-Control Study

     First, SelectFirst, Select

      CHD CasesCHD Cases ControlsControls

Then, Measure Then, Measure Past ExposurePast Exposure

SmokersSmokers 112 112 (a)(a) 176 176 (b)(b)

NonsmokersNonsmokers 88 88 (c)(c) 224 224 (d)(d)

   TotalsTotals 200 200 (a + c)(a + c) 400 400 (b + d)(b + d)

   Proportions Proportions smoking smoking cigarettescigarettes

56%56% 44%44%

     

Analysis in Case-Control StudiesAnalysis in Case-Control Studies

Odd Ratio (OR) – crude and adjusted (from multivariate Odd Ratio (OR) – crude and adjusted (from multivariate statistical analysis)statistical analysis)OR ~= RR when disease is rare and cases/controls representative OR ~= RR when disease is rare and cases/controls representative of all cases/population with regard to exposure. of all cases/population with regard to exposure.

Interpretation of an Odds Interpretation of an Odds Ratio (OR)Ratio (OR)

OR=1 implies no association.OR=1 implies no association.

Assuming statistical significance: Assuming statistical significance: – OR = 2 suggests cases were twice as likely as OR = 2 suggests cases were twice as likely as

controls to be exposed, or cases were 2 times controls to be exposed, or cases were 2 times more likely to be exposed than controls. more likely to be exposed than controls.

Above Example: Patients with CHD were 1.62 Above Example: Patients with CHD were 1.62 times more likely to be smokers than controls times more likely to be smokers than controls without CHD. without CHD.

– OR < 1 suggests a protective factor. OR < 1 suggests a protective factor.

What is a cohort?What is a cohort?

A cohort is defined as a population A cohort is defined as a population group, or subset thereof, that is group, or subset thereof, that is followed over a period of time.followed over a period of time.

The term cohort is said to originate The term cohort is said to originate from the Latin cohors, which referred from the Latin cohors, which referred to one of ten divisions of an ancient to one of ten divisions of an ancient Roman legion.Roman legion.

What is a cohort? What is a cohort? (cont’d)(cont’d)

Cohort group members experience a Cohort group members experience a common exposure associated with a common exposure associated with a specific setting (e.g., an occupational specific setting (e.g., an occupational cohort or a school cohort) or they cohort or a school cohort) or they share a non-specific exposure share a non-specific exposure associated with a general associated with a general classification (e.g., a birth cohort—classification (e.g., a birth cohort—being born in the same year or era).being born in the same year or era).

COHORT STUDIESCOHORT STUDIES

Follow-up studies, longitudinal studies, and incidence Follow-up studies, longitudinal studies, and incidence studiesstudies

Cohort study is the method in which Cohort study is the method in which subsets of a defined population can be subsets of a defined population can be identified who are, have been, or in the identified who are, have been, or in the future may be exposed or not exposed future may be exposed or not exposed to a factor or factors hypothesized to to a factor or factors hypothesized to influence the probability of occurrence influence the probability of occurrence of a given disease or other outcome.of a given disease or other outcome.

Historical Cohort StudiesHistorical Cohort Studies

Retrospective Cohort Studies. Retrospective Cohort Studies.

When the cohort(s) are assembled from When the cohort(s) are assembled from past records. Follow-up can be either in the past records. Follow-up can be either in the present or from more recent past records.present or from more recent past records.

Historical cohort studies may study either Historical cohort studies may study either general population cohorts or specific general population cohorts or specific exposure cohorts.exposure cohorts.

Structure of a Cohort StudyStructure of a Cohort Study

SOURCE POPULATION

RANDOM SAMPLING

NON-CASES

PREVALENT CASES

DISEASE

NO DISEASE

DISEASE

NO DISEASE

EXPOSED

NON-EXPOSED

FOLLOW-UP OUTCOME

Design of cohort studyDesign of cohort study

TIMETIME

ExposureExposure DiseaseDisease

Study groupStudy group PresentPresent

Comparison Comparison

GroupGroup AbsentAbsent

Disease rate for exposedDisease rate for exposed = a= a

a + ba + b

for nonexposedfor nonexposed = c= c

c + dc + d

aa

a+ ba+ b

Relative Risk =Relative Risk = c c

c+ dc+ d

Present

Present

Absent

Absent

a

b

c

d

Design of a Cohort StudyDesign of a Cohort StudyStart with a group of subjects who Start with a group of subjects who lack a positive history of the lack a positive history of the outcome of interest and are at risk outcome of interest and are at risk for the outcome.for the outcome.

Include at least two observation Include at least two observation points: one to determine exposure points: one to determine exposure status and eligibility and a second status and eligibility and a second (or more) to determine the number (or more) to determine the number of incident cases.of incident cases.

Design of a Cohort StudyDesign of a Cohort Study(cont’d)(cont’d)

Permit the calculation of incidence Permit the calculation of incidence rates.rates.

Can be thought of as going from Can be thought of as going from causecause to to effecteffect..

Involve the collection of primary Involve the collection of primary data.data.

If we observe an association between an exposure and a disease or another outcome, the question is:

Is the association causal?

Design of a cohort study.

Prospective Cohort StudyProspective Cohort Study

Purely prospective in nature; Purely prospective in nature; characterized by determination characterized by determination of exposure levels at baseline of exposure levels at baseline (the present), and follow-up for (the present), and follow-up for occurrence of disease at some occurrence of disease at some time in the future.time in the future.

Figure 9-6. Time frame for a hypothetical prospective cohort study begun in 2004.

Advantages of Prospective Advantages of Prospective Cohort StudiesCohort Studies

Enable the investigator to collect Enable the investigator to collect data on exposures; the most direct data on exposures; the most direct and specific test of the study and specific test of the study hypothesis.hypothesis.

The size of the cohort is under The size of the cohort is under greater control by the investigators.greater control by the investigators.

Advantages of Prospective Advantages of Prospective Cohort Studies Cohort Studies (cont’d)(cont’d)

Biological and physiological assays can be Biological and physiological assays can be performed with decreased concern that the performed with decreased concern that the outcome will be affected by the underlying outcome will be affected by the underlying disease process (e.g., cholesterol levels or disease process (e.g., cholesterol levels or nutrient levels).nutrient levels).

Direct measures of the environment (e.g., Direct measures of the environment (e.g., indoor radon levels, electromagnetic field indoor radon levels, electromagnetic field radiation, cigarette smoke concentration) radiation, cigarette smoke concentration) can be made in order to define exposures can be made in order to define exposures precisely.precisely.

Retrospective Cohort StudyRetrospective Cohort Study

Despite substantial benefits of Despite substantial benefits of prospective cohort studies, prospective cohort studies, investigators have to wait for cases investigators have to wait for cases to accrue.to accrue.

Retrospective cohort studies make Retrospective cohort studies make use of historical data to determine use of historical data to determine exposure level at some baseline in exposure level at some baseline in the past.the past.

Time frame for a hypothetical retrospective cohort study begun in 2004.

Figure 9-8. Time frames for a hypothetical prospective cohort study and a hypothetical

retrospective cohort study begun in 2004.

Advantages of Retrospective Advantages of Retrospective Cohort StudiesCohort Studies

A significant amount of follow-up may A significant amount of follow-up may be accrued in a relatively short period be accrued in a relatively short period of time.of time.

The amount of exposure data collected The amount of exposure data collected can be quite extensive and available to can be quite extensive and available to the investigator at minimal cost.the investigator at minimal cost.

Prospective cohort study (Framingham Heart Study)Prospective cohort study (Framingham Heart Study)

5,889 subjects aged 30 or older (mean age 55 years, 5,889 subjects aged 30 or older (mean age 55 years, 54% women) included54% women) includedFree of heart failure at the baseline examination (in Free of heart failure at the baseline examination (in 1976-79, and offspring in 1979-83)1976-79, and offspring in 1979-83)Followed them up to the year 2001 (mean 14 years)Followed them up to the year 2001 (mean 14 years)To ascertain the occurrence of new heart diseaseTo ascertain the occurrence of new heart diseaseCalculate the cumulative incidence of heart disease, Calculate the cumulative incidence of heart disease, age-adjusted incidenceage-adjusted incidenceCalculate the relative risk (hazard ratio) of heart Calculate the relative risk (hazard ratio) of heart disease in those obese subjects compared to those disease in those obese subjects compared to those with normal weight. with normal weight. Results: RR = 1.39 (95% CI: 1.12-1.72) for overweight, Results: RR = 1.39 (95% CI: 1.12-1.72) for overweight, and 1.98 (1.54-2.56) for obese subjects, compared with and 1.98 (1.54-2.56) for obese subjects, compared with subjects with normal weight (reference group). subjects with normal weight (reference group).

Smoking and Coronary Heart Disease (CHD): A Smoking and Coronary Heart Disease (CHD): A Hypothetical Cohort Study of 3,000 Cigarette Hypothetical Cohort Study of 3,000 Cigarette

Smokers and 5,000 NonsmokersSmokers and 5,000 Nonsmokers

  

CHD CHD DevelopsDevelops

CHD Does CHD Does Not Not

DevelopDevelop TotalsTotals

Incidence Incidence per 1,000 per 1,000 per Yearper Year

Smoke Smoke cigarettescigarettes

8484 2,9162,916 3,0003,000 28.028.0

Do not smoke Do not smoke cigarettescigarettes

8787 4,9134,913 5,0005,000 17.417.4

Relative Risk (RR) = 28.0/17.4 = 1.61. Relative Risk (RR) = 28.0/17.4 = 1.61.

Risk Calculation in a Cohort StudyRisk Calculation in a Cohort Study

    

Then Follow to See Whether or not the outcome occursThen Follow to See Whether or not the outcome occurs    

     Disease Disease

DevelopsDevelops

Disease Disease Does Not Does Not DevelopDevelop TotalsTotals

Incidence Incidence Rates of Rates of DiseaseDisease

First SelectFirst Select

ExposedExposed aa bb aa + + bb a/(a+b)a/(a+b)

Not Not exposedexposed

cc dd cc + + dd c/(c+d)c/(c+d)

   Incidence in exposed = Incidence in exposed = a/(a+b)a/(a+b)

Incidence in non exposed = Incidence in non exposed = c/(c+d)c/(c+d)

Relative Risk in Cohort Relative Risk in Cohort StudyStudy

Relative Risk (RR) - provides Relative Risk (RR) - provides information on the relative effect information on the relative effect of the exposure on the disease. of the exposure on the disease. RR= _RR= _risk in exposed____ risk in exposed____

risk in nonexposedrisk in nonexposedIndicates how many times higher Indicates how many times higher or lower the disease risk is or lower the disease risk is among the exposed as compared among the exposed as compared to the unexposed. to the unexposed. Is commonly used in Is commonly used in etiologic/incidence research.etiologic/incidence research.

Relative Risk (RR) of a Disease Relative Risk (RR) of a Disease

If RR = 1If RR = 1 Risk in exposed equal to risk in Risk in exposed equal to risk in nonexposed (no association)nonexposed (no association)

If RR > 1If RR > 1 Risk in exposed greater than risk in Risk in exposed greater than risk in nonexposed (positive association; nonexposed (positive association; possibly causal)possibly causal)

If RR < 1If RR < 1 Risk in exposed less than risk in Risk in exposed less than risk in nonexposed (negative association; nonexposed (negative association; possibly protective)possibly protective)

Relative merits: cohort studiesRelative merits: cohort studiesAdvantagesAdvantages

Clear temporal Clear temporal relationshiprelationship

Least susceptible to Least susceptible to some forms of biassome forms of bias

Can examine multiple Can examine multiple predictors of outcomepredictors of outcome

Efficient for rare Efficient for rare exposuresexposures

Useful when RCT Useful when RCT infeasible, unethicalinfeasible, unethical

DisadvantagesDisadvantages

No control over No control over predictor (vs. RCT)predictor (vs. RCT)– confoundingconfounding

Inefficient for rare or Inefficient for rare or long-latent diseaseslong-latent diseases

Loss to follow-up Loss to follow-up threatens validitythreatens validity

Potential bias in Potential bias in outcome ascertainmentoutcome ascertainment

Relatively resource- and Relatively resource- and time-intensivetime-intensive

ClinicalClinical trial designtrial design

Estimate of effect is rate (risk) of outcome in treatment vs. control (e.g. risk[treatment]/risk[control])

Study population

Treatment No treatment(usual care, placebo)

NoYes NoYes

follow-up period

outcome of interest

Random assignment by

investigator

Relative merits: clinical trialsRelative merits: clinical trialsAdvantagesAdvantages

strong claims for strong claims for causalitycausality

control of most bias, control of most bias, confoundingconfounding

tight control on tight control on exposure/treatmentexposure/treatment

high internal validityhigh internal validity

possible to examine possible to examine multiple outcomesmultiple outcomes

DisadvantagesDisadvantages

time consumingtime consuming

expensive, resource expensive, resource intensiveintensive

compliance, drop-outcompliance, drop-out

sometimes severe ethical sometimes severe ethical constraintsconstraints

may not mirror practicemay not mirror practice

generalizability may be generalizability may be limited (i.e. selection bias)limited (i.e. selection bias)

Hierarchy of EvidenceHierarchy of Evidence

Meta-analysisMeta-analysisHierarchy of Research Design QualityHierarchy of Research Design Quality– Randomized, prospective, community and/or clinical Randomized, prospective, community and/or clinical

trial (Cochrane and Campbell collaborations)trial (Cochrane and Campbell collaborations)– Cohort studiesCohort studies– Case-control studiesCase-control studies– Cross-sectional studies (prevalence studies)Cross-sectional studies (prevalence studies)– Descriptive/ecologic (correlation) studiesDescriptive/ecologic (correlation) studies– Case series/case reportsCase series/case reports– Individual evidence (personal experience/expert opinion)Individual evidence (personal experience/expert opinion)

QuestionsQuestions