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Outline
Background and Definitions g Study Designs in Pharmacoepidemiology
Randomized controlled trials Observational studies
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A desire to take medications is, perhaps, the greatest feature which distinguishes man from di ti i h f other animals. animals.
Sir William Osler 1891 Osler,
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Pharmacoepidemiology
Pharmacologystudy of the effects of drugs g Clinical Pharmacologystudy of the effects of drugs in humans g
Pharmacokineticsbody effect on the drug Pharmacodynamicsdrug effect on the body
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Pharmacoepidemiology
Focus of inquiry is clinical pharmacology using the methods of epidemiology
Epidemiology Population:
Taco eaters
Pharmacoepidemiology Population:
HTN patients
Exposure:
Green peppers
Exposure:
ACE inhibitors
Outcome:
Infection
Outcome:
Cough
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Pharmacoepidemiology
the study of the use and effects of medications in populations pp the application of the methods of clinical epidemiology to address the subject matter of clinical pharmacology h l the science underlying the public health practice of drug safety surveillance
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Case-Control Study Descriptive Studies p Analyses of Secular Trends Case Series Case Reports
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Case-Control Study Descriptive Studies p Analyses of Secular Trends Case Series Case Reports
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Background: Uncertain risk/benefit of HRT in women despite observational data This trial found that, compared with placebo, women receiving estrogen plus progestin experienced i i t l ti i d
increased risk of myocardial infarction increased risk of stroke increased risk of blood clots, including DVT and PE clots increased risk of breast cancer decreased risk of colorectal cancer fewer fractures
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Background: Experimental and observational data suggest PPI therapy may reduce the protective effect of clopidogrel against coronary artery disease
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Say what?
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Metaanalysis of RCTs
Metaanalysis of 42 trials In the rosiglitazone group, as compared with the control group, t l OR for myocardial infarction 1.43 (95% CI 1.03 to 1.98) OR for CV death 1.64 (95% CI, 0.98 to 2.74)
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Exposur re
A C
B D
Absent Ab
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Cohort Study
persontime
26 14 17 26
NonNon random process
Exposed Unexpose d
26 22 24 20 26 26
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Study y population
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The sophisticated use and understanding of f case-control case control studies is the most outstanding
methodologic
because it need not be extremely expensive nor timeconsuming to conduct a casecontrol study, many studies have study been conducted by would-be would be investigators who lack even a g rudimentary appreciation for epidemiologic principles. id i l i i i l Kenneth J Rothman J.
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Case-control study: The observational y epidemiologic study of persons with the disease of interest and a suitable control group of persons without the disease. The relationship of an attribute [risk factor] to the disease is examined by comparing the diseased and nondiseased with regard to how frequently the attribute [risk factor] is present.
John M. Last, Dictionary of Epidemiology CCEB
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Case-control Study C t l St d
Source Population Outcome A Study sample
Observed outcome
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If a case-control study is conducted within an enumerated d t d ithi t d source population (which minimizes the possibility of selection bias), it can be thought of as a nested case-control study.
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Source Cohort
The "source cohort" behind a case-control study is casethe population (cohort) that gave rise to the cases included in the study. study Example: E l Cases: Cases: lung cancer cases listed in the cancer registry g g y of the State of Pennsylvania Source cohort: ? cohort:
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Selection of Cases
Ideally include all the cases in the defined population however in practice rarely done (and not necessary to draw valid conclusion). Most studies use sample of patients selected from some convenient source: often from persons seeking medical care for the disease disease. Better to use incident rather than prevalent cases.
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Selection of Controls
Controls are people who do not have the disease but are otherwise comparable to the cases. p Need to pick subjects who would have become cases in the study had they developed the disease: i.e. they are representative of the underlying p p population. Must be selected independent of exposure status.
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Odds Odd
The ratio of the probability of an occurrence of an event to that of nonoccurrence Any ratio of two natural numbers can be regarded as an odds:
Total: 50 Exposed: 20 Unexposed: 30 Odds of exposure: 20/50 divided by 30/50; or 20/30
Exposure odds
Ratio of those exposed to those who are not exposed
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D
b d
Total a + b c + d
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Cumulative Case-Control Design CaseMost familiar type of case-control design caseControls can be thought of as a sample of the source cohort who were diseasediseasefree at the end of follow-up (i.e., followsurvivors) survivors Called survivor sampling by some sampling authors
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What Measures Do We Need to Estimate an Exposure Odds Ratio for the Source Cohort?
Odds of EXPOSURE in diseased Odds of EXPOSURE in non-diseased non-
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EXPOSED
a c
b d
UNEXPOSED
C
N1
D
N0
UNEXPOSED
n1 n0 If cases are representative of diseased in source p p population, then a/c (exposure odds) , ( p ) estimates A/C If controls are representative of non-diseased in representative nonsource population at the end of follow-up, then b/d follow(exposure odds) estimates B/D
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Exposure Odds Ratio in a Case-Control Study CaseEXPOSURE odds in CASES = EXPOSURE odds in CONTROLS a c a b ad = = = b d c d bc
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Conditions
The exposure odds ratio is an estimate of the measure of association possible from a cohort study if the following f ll i conditions are met: diti t 1. Cases are representative of diseased in source 1 C t ti f di di cohort, then a/c (exposure odds) estimates A/C 2. Control are representative of disease-free in source diseasecohort, then b/d (exposure odds) estimates B/D cohort
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Odds
odds = probability / (1 probability) odds = risk / (1 risk) If risk << 1.0, then odds risk
Risk Odds 0.010 0 010 0.010 0.050 0 050 0.053 0.100 0 100 0.111 0.20 0 20 0.25 0.80 0 80 4.00
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The disease must be rare in order to estimate RR Assumes no differences in follow-up followrates among the exposed and unexposed Best it d f B t suited for a short latency period h tl t i d between exposure and outcome
E.g., acute epidemic setting E t id i tti
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What if the disease outcome is not rare? What if there is a long latency period between exposure and outcome and differential follow up follow-up among patients? Wh t if you want to estimate the What tt ti t th incidence rates?
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Cohort Study
persontime
26 14 17 26
NonNon random process
Exposed Unexpose d
26 22 24 20 26 26
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Study y population
PersonTime
26+17+26+24+26= 26 17 26 24 26
119
14+26+22+20+26=
108
Ratee = 2 119 = 0 0168 events/time units 0.0168 Rate = 3 108 = 0.0278 events/time units Rate Ratio = 0 0168 0 0278 = 0 60 0.0168 0.0278 0.60
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PersonTime
26+17+26+24+26= 26 17 26 24 26
119
14+26+22+20+26=
108
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n1
The OR from incidence density sampling is incidence sampling equivalent to the rate ratio (no rare disease p ) assumption needed)
Incidence Rate of DISEASE in EXPOSED IRR= -----------------------------------------------------------------Incidence Rate of DISEASE in UNEXPOSED Exposed cases / Person-time (exposed) Person= -----------------------------------------------------------------Unexposed cases / Person-time (unexposed) PersonExposed cases / unexposed cases E d d = --------------------------------------------------------------------PersonPerson-time (exposed)/Person-time (unexposed) (exposed)/PersonExposure odds in DISEASED = --------------------------------------------------------------------------------------------------------------Exposure odds in Person-time (either in the entire cohort or a sample of the Personcohort)
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UNEXPOSED
c n1
d n0
If cases are representative of diseased in source cohort, then a/c (exposure odds) , ( p ) estimates A/C If controls are representative of total personrepresentative persontime in source cohort, then b/d (exposure odds) estimates Y1/Y0
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How Do We Obtain a Representative Sample of Total Person-Time at Risk i th S Ri k in the Source Population? P l ti ?
Density sampling: Select one or more controls from sampling: remaining disease-free members of the source diseasecohort at the instantaneous time period in which instantaneous each case occurs
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Case-Control Study
controls sampled
Exposed Unexpose d
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Study y population
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Case-Control Study
controls sampled
1 2 3 4
NonNon random process
2 3 86
Exposed 5 Unexpose 7 d 8 9 10 6
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Study y population
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IRR = (2 / 119) (3 / 108) = 0.60 = (2 / 3) (119 / 108) Equal (2 / 3) (8 / 7) = 0.58 ( ) ( ) e cep o except for
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Choice of Design
Hybrid Design y g
Retrospective Cohort analysis
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Thiazides
Random allocation
No thiazides
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Thiazide s No thiazides
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Get outcome info on 108,000 subjects. Get exposure & confounder i f on 386 cases + Controls f d info 386 controls. sampled
Thiazide s No thiazides
Data from Herings RMC, J Clin Epidemiol 1996;49:115-19 Cli E id i l 1996 49 115 19
femur fracture no femur fracture
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(cases) (controls) thiazides 46 70 116 no thiazides 340 316 656 total 386 386 772 Odds ratio = (46 / 340) (70 / 316) Or, to make math easier, (46 316) / (70 340) = 0.6 = unbiased estimate of rate ratio The rate of femur fracture is 40% lower in thiazide users than non-users (assuming no confounding).
total
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Pharmacoepidemiology Part II at
Caveats and Pitf ll C t d Pitfalls
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Outline
Bias Confounding o eg s /be e t at o How to weigh risk/benefit ratio
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Selection Bias
A distortion in the estimate of occurrence or effect resulting from the manner in which subjects are selected for the study
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Study question:
Does therapy with 6MP increase the risk of l k i k f leukopenia? i ?
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Design
Cohort study of IBD patients treated with 6MP compared to IBD patients not ith dt ti t t treated with 6MP S Setting: Health plan participants with 6MP
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Misclassification
Exposure misclassification Outcome misclassification Differential vs. non-differential vs non differential misclassification
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Actual consumption vs. prescription Date prescribed date exposure started p p Days supplied duration of exposure
How to handle overlapping dispensing periods?
Plausible latency period between exposure and outcome Availability of OTC exposure
Example: Aspirin/NSAIDs
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Example
Statin use may reduce the risk of colorectal cancer l t l Primary definitions of statin exposure in published studies
Any prescription of statin within the past 12 month th Cumulative duration of statin use >5 years
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Defining Outcomes/Cases
Rule-out diagnosis vs. actual diagnosis Prevalent vs. incident diagnosis
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Defining Outcomes
Validity of the diagnosis
Direct validation (paper record review, physician or patient survey, etc.) C Corroborative procedures/treatment b ti d /t t t
Example: colon cancer, colorectal surgery, chemo
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Exposure misclassification errors are independent of errors in other variables in the analysis
E.g., one measure from a comprehensive questionnaire
Ab Absence of i t f interactions with other sources of ti ith th f systematic error, e.g., selection bias and g confounding CCEB
It probably is incorrect to claim (as authors often do) that the estimate from a study must be an underestimate because the bias is towards the null.
Probably better to say the estimate is more likely to be below the true estimate than above it
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Difference in life expectancy: 79.7 vs. 75.8 years; P = 0.003 r 0 003 28% Reduction in risk of death per year!!
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Birth
Death
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Time
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Results: Statin associated with 45% reduction in lung cancer risk (adjusted OR 0.55, 95% CI: 0.52-0.59). CCEB
Khurana et al. Chest. 2007;131:12821288
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Secondary hypergastrinemia g
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Duration of Controls N Crude OR (95% Cases N (%) PPI (%) CI) NonNon-users 3,663 (82.7) 39,159 (88.4) Reference < 1 year Recent 400 (9.0) 1,663 (3.8) 2.6 (2.3-2.9) (2.3Past 211 (4.8) 2,017 (4.6) 1.1 (1.0-1.3) (1.01-2 years 67 (1.51) (1 51) 573 (1.3) (1 3) 1.3 (1.0-1 6) 1 3 (1.0-1.6) (1 0 2-3 years 34 (0.8) 385 (0.9) 1.0 (0.7-1.4) (0.73-4 years 24 (0.5) 211 (0.5) 1.2 (0.8-1.9) (0.84-5 years 17 (0.4) 140 (0.3) 1.3 (0.8-2.2) (0.8>5 years 16 (0.4) 144 (0.3) 1.2 (0.7-2.0) (0.7-
Adjusted OR (95% CI) Reference 2.6 (2.3-2.9) (2.31.1 (0.9-1.3) (0.91.2 (0.9-1.6) 1 2 (0.9-1 6) (0 9 0.9 (0.6-1.3) (0.61.1 (0.7-1.7) (0.71.1 (0.7-1.9) (0.71.1 (0.7-1.9) (0.7-
Protopathic bias? p
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Protopathic bias
Use of the drug to treat early signs of the t th outcome
Early symptoms of CRC leading to PPI use
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Protopathic Bias
How to address it?
Lag-time approach: a specific time period before the date of diagnosis with the disease under study would be excluded from the exposure assessment But what is the optimal lag-time? 6 p g months? 12 months? Should it be dependent on the outcome?
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Confounding in Pharmacoepidemiology
Confounding by indication
Examples Measures to address confounding by indication i di ti Channeling
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Confounding may be considered to be a mixture of effects. Specifically, the i t f ff t S ifi ll th estimate of the effect of the exposure of interest is distorted because it is mixed with the effect of an extraneous factor.
(Rothman)
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Confounding of an g Association
Confounder
Medication
Outcome
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Causal Pathway
Factors in the causal pathway are not confounders (more on this later) f d ( thi l t )
Medication
Causal pathway
Outcome
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Study Question
Is PPI therapy a risk factor for hip fractures? f t ? Ways to do the study
RCT
May be unethical to randomize
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Design
Methods M th d
Cases
Incident hip fracture cases
Controls
Incidence density sampling Matched on sex, index date, year of birth, date of the beginning of UTS follow-up and d b i i f f ll d duration of UTS follow-up ti f f ll before index date
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4 years
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Effect of Dosage
>1 yr H2RA Average Daily dose >1 yr PPI Average Daily dose QD 1.4 (1.3-1.5) (1.3BID 2.7 (1.8-3.9) (1.8-
Low
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Targownik et al.
CMAJ
2008;179(4):319-26
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Analysis stage
Stratified analyses y Mathematical modeling
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Conclusion PPI therapy is not associated with hip fracture risk in patients without major RFs for fractures
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Generalizability
80% of hip fractures excluded
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Confounder C f d
Used to restrict cohort
PPI
Intermediate
Osteoporosis, B-12 deficiency, etc B-
Will bias towards the null Generally NOT used to restrict cohort
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Hip Fracture Hi F t
Mathematical Modeling
Mantel Haenszel methods Logistic regression Linear regression Cox proportional hazard regression Etc.
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What do the results of a multivariable model mean? It is a measure of the association of each variable with the outcome of interest after adjusting for all other variables in the model i bl i th d l
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Pitfalls of Modeling
Ignoring the stratified results
Co-linear variables Co Absence of overlap
Too many variables Adjusting for variables in the causal pathway Adjusting for variables that are not confounders
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Pitfalls of Modeling
Assuming that modeling can correct problems with the data t bl ith th d t collection
You cant turn garbage into gold with statistics
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Channeling
What is channeling?
Definition: Drugs with similar therapeutic indications are prescribed to groups of patients with prognostic differences Can lead to confounding by indication
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Channeling
A study comparing patients started on COX-2 inhibitors after their initial marketing vs. those remaining on NSAIDs in 1998-1999
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Office work
Firefighter
10.6
36.1
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Commercial plane Car Additional risk from talking on cell phone Motorcycle CCEB Cohen JT. Health Affairs 2007:26:636-46 2007:26:636-
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Conclusions
All drugs can cause adverse reactions d d ti Observational drug surveillance studies have an important role in assessing safety of medications The validity of observational drug surveillance studies depends on
Appropriate choice of study design Appropriate definition of exposure and outcome Addressing potential biases and confounding
A Acceptability of risk depends on potential t bilit f i k d d t ti l benefits, alternative therapies, patient tolerance CCEB
Questions?
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