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Clinical Research and Epidemiology
Robert S. Sandler, M.D., M.P.H.University of North CarolinaChapel Hill, North Carolina
What is epidemiology?
Epidemiology● Study of the distribution and determinants of disease
in populationsClinical epidemiology
● Science of making predictions about individual patients using the tools of epidemiology
History
John Snow Map of cholera cases 1854
History
Epidemiology today
N Engl J Med 2012;367:1704-13
Epidemiology today
N Engl J Med 2012;367:1704-13
Williamsburg
Crown Heights
Borough Park
IBD is a challenge for epidemiologists
Epidemiologic methods work great when● Acute onset illness – cholera, mumps● Point source – Broad Street pump, yeshiva● Rare illness cluster – angiosarcoma of the liver and
vinyl chloride
IBD● Gradual onset in children and adults● Persists for years● No known etiology
Spectrum of epidemiologic research
Disease burden (how many/how much)Etiology risk factors for disease)Diagnosis (evaluation of medical tests)Natural history/prognosis
● What happens to people with disease● Risk factors for disease outcomes
Treatment effects● Intended● Unintended
Methods of clinical research
Observational Studies● Investigators just observe (measure) exposures and
outcomesInterventional Studies
● Investigators assign exposure and measure outcomes (clinical trials of drugs or surgery)
Observational Studies
“You can observe a lot just by watching.” - Yogi Berra
DescriptiveAnalytical
● Cross-sectional● Cohort● Case-control
Descriptive Studies
Burden of Disease● Incidence – how many new cases/time● Prevalence – how many cases currently● Morbidity● Mortality● Costs● Days of work/school lost (disability days)
Descriptive studies
Incidence Prevalence
Prevalence ~ incidence x duration
Analytical studies
Associations between exposures and outcomes● Is smoking (or diet) associated with risk of IBD?● Are specific genes associated with risk of IBD?● Are results of a diagnostic test associated with diagnosis
of IBD?● Is treatment X associated with improvement in Crohn’s
disease activity● Is treatment Y associated with a particular side effect?● Is diet (or other lifestyle factors) associated with IBD
flares?
Cross-sectional studies
Source Population
Sample
Outcome? Exposure?
Exposure and outcome measured at same time
Cross-sectional
Assemble study populationMeasure IBD status (yes/no)Measure smoking (yes/no)Find that people with Crohn’s more likely to smoke
● i.e. smoking (exposure) is associated with CD (outcome)
Advantages: Quick and inexpensiveDisadvantages:
● No temporality● Cannot differentiate cause and effect
Cross-sectionalCCFA Partners: Internet based research study>12,000 individuals with IBD completed an online survey about steroid use and many patient outcomes
Cohort study
Measure exposure
Time
Exposed
Unexposed
Disease
Disease
Study begins here
Baseline
Cohort study
Assemble study population free of diseaseMeasure smoking (yes/no)Follow study population for long timeIdentify those who develop IBDCompare incidence (# new cases) of IBD in smokers vs nonsmokersAdvantages: Can identify temporal relationship, assess causality, determine incidenceDisadvantages:
● Long follow-up needed ($$$$$$$)● If outcome is rare (IBD), need very large population
NSAIDs and Aspirin
Nurses’ Health Study I is a prospective cohort of 121,700 U.S. female registered nurses, aged 30 to 55 years
Aspirin/NSAID use ascertained by self-report
Over 1,295,317 person-years of follow-up
123 cases of CD and 117 cases of UC
Ananthakrishnan, Annals Internal Medicine, 2012
CD UCNSAID > 15 days/month
1.6 (1.0-2.6) 1.9 (1.2-3.0)
Aspirin > 15 days/month
1.0 (0.6-1.5) 1.0 (0.6-1.7)
Case-control study
Time
Exposed?
Exposed?
Disease
NoDisease
Study begins here
Case control studyMatch cases (people with outcome (IBD)) to controlsMeasure prior exposuresCompare exposures in cases and controls
● Are IBD cases more likely to report low fiber intake in past than controls
Advantages: ● Good for rare diseases● More efficient (time and sample size, ↓$$$$)● Can identify temporal relationships
Disadvantages: ● Recall of exposure● Sample selection (cases and controls should arise
from same population)
Case control study of potential risk factors for IBD
Bernstein, Am. J. Gastro, 2006
Cases with CD (n = 364) and UC (n = 217), ages 18-50 yrControls were drawn from Manitoba Health Subjects were administered a multi-item questionnaire
What do statistics tell us?
Magnitude of effectPrecision of resultsStatistical significance - role of chanceStatistical significance not clinical significance
Potential pitfalls: validity and bias
Internal validity: degree to which the study findings reflect the truth
● Bias: Systematic difference between observed findings and the truth
● Chance● Statistics assess role of chance, but do not
address biasExternal validity: degree to which the study findings are applicable to other populations
Types of biasSelection/referral bias
● Distortion in the results due to a difference b/t subjects who participated and those who did not
Measurement bias● Distortion in results due to error in measurement
of the exposure, outcome or both
Outcome(ulcer)
Exposure(smoking)
Confounding
Confounder(alcohol)
DirectEffect
IndirectEffect
Clinical trial
Study population
Intervention ‘A’
Intervention ‘B’
Outcome
Outcome
StandardizedFollow-up
&Co-interventions
What does randomization accomplish?
If treatments are assigned at random, then:● Treatments are unrelated to patient characteristics● Achieves balance among different treatment groups
(same mix of smokers, disease severity, across groups)
● No confounding● Even if confounder not known or measured!
Clinical trial
● 526 patients randomly assigned to receive intravenous ustekinumab or placebo
● Primary outcome (end point) was a clinical response at 6 weeks
Clinical trial
Clinical trial
Why Placebo?
If patients know they are getting a study medication, they may feel betterIf doctors know their patients are getting a medication, they may perceive them as doing better“Double-blind, placebo-controlled”
● All subjects get something● Neither subjects nor investigators know what
Randomization and concealed allocation required to prove efficacyRequired by FDA
Ethical considerations
Honest disagreements exist about the preferred treatment of the condition (equipoise)
● Neither intervention/treatment should be considered inferior, or potentially harmful
The RCT must produce results which are convincing enough to resolve the dispute
● Makes the patients’ participation is worthwhile
Comparative Effectiveness Research
If all we have is placebo controlled trials, then we don’t know
● What medicines are more effective than others● What medicines are safer than others
We need head-to-head comparisons, but● Pharma often not willing to take the risk● FDA not require it
Observational studies?
Clinical Effectiveness Research
Patients who enroll in clinical trials are:● Young to middle aged adults● Free of co-morbidity (other health problems)● Cared for at large research hospitals
What about. . .● Kids● Elderly● Those with other health conditions
Observational studies?
Safety
Clinical trials too small to assess medication safety● 51% of drugs have label changes due to major safety
issues discovered after marketing● 20% of drugs get new “black box” warnings after
marketing● 4% of drugs are ultimately withdrawn for safety
reasons
Incidence
90%
95%
99%5000
4000
3000
2000
1000
1/1001/10 1/1000
Too Small
37
Num
ber o
f exp
osed
Probability of detection
LymphomaREACH n=212CERTIFI n=526
Safety research
Objective: To determine whether initiation of TNF- antagonists compared with immunomodulators is associated with an increased risk of serious infections requiring hospitalizationMethods: Cohort study using de-identified data from insurance companiesFor IBD, TNF- antagonist initiators compared to 6MP/AZA initiators, matched by propensity score
Grijalva, JAMA, 2011
Hospitalization for Infection
No difference in hospitalizations for infectionMean age 58 (versus 35 in SONIC)
What makes a good study
Is there a primary research question?Is the research question important?Is the study design appropriate to the research question?Are the investigators qualified?Is the study population well-defined?Are exposures and outcomes well-defined?Feasible?
● Sample size needed relative to time and budget?● Barriers for recruitment
Burden (for patients and providers) Pool of eligible subjects Competing studies
Ethical?
Review
Conclusion
Broad spectrum of clinical and epidemiological research: burden, etiology, diagnosis, prognosis, treatment effectsMany study designs
● Advantages and disadvantages to each
Focused and highly relevant clinical question essentialMany pitfalls to be considered
● Bias● Ethics● Practical considerations