Pharmacogenetics

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Cohort Studies, Nested Case-Control Studies,
Relative Risks Brian F. Gage, MD,
MSc Department of General Medical Sciences
Associate Professor of Medicine September 17,
2008
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Case-Control Studies
Study Onset
Time
Exposed
Cases
Unexposed
Exposed
Controls
Unexposed
Direction of Inquiry
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Cases

• Typically have a rare disease
• Identified and selected from a defined source
  population (e.g., all patients from a clinic,
  hospital, HMO, state, or nation)
• Likelihood of a case being included in study must
  not depend on exposure to risk factor
• Criteria for defining cases should be sensitive
  and specific

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Controls

• Identified and selected from the same source
  population as the cases
• Chosen at random from source population
• An exposed member of the population should have
  the same chance of becoming a control as an
  unexposed member

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Assessing Exposure

• Interviews and questionnaires often used
• Objective measures limit bias
• e.g. Genotype, biological markers
• e.g. Biological markers
• Many exposures dont have biological markers
• Biological marker may not be present when test is
  taken (e.g., alcohol is quickly metabolized)
• e.g. Pharmacy records of drug exposure
• Adding an addl risk factor may allow one to
  quantify potential bias
• E.g. esophageal squamous cell CA in GERD study

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Case-Control Studies

• Pros
• Efficient (esp. for rare outcomes)
• Faster
• Cheaper
• Allow for multiple risk factors to be assessed
• Provide for an OR (ad/bc), which estimates RR.
• Cons
• Bias (systemic error)
• Sampling bias (e.g. cases referred to BJH)
• Ascertainment bias (e.g. looking harder at cases)
• Recall bias (e.g. new mom recalls pregnancy
  habits)
• Differential measurement bias (blinding can
  minimize)
• Temporal association is unclear
• Only 1 outcome can be studied
• Does not yield incident rates

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Study Designs

• Cohort study
• Prospective
• Retrospective
• Fancy Case-control studies
• Nested case-control study
• Case-cohort study
• Case-crossover study
• Miscellaneous studies
• Clinical trial
• Intervention study
• Other (e.g., ecological study, case study, and
  case series)
• 10 slides adapted from UNC Epi 101
• www.sph.unc.edu/epid/course/Webpage/epid168/study_
  designs.ppt

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Cohort Studies
Onset of prospective study
Onset of retrospective study
Time
Eligible subjects
Disease
Exposed
No Disease
Disease
Unexposed
No Disease
Direction of inquiry in a prospective cohort study
8 slides adapted from Ty Borders, Ph.D course on
managerial epidemiology lthttp//www.ttuhsc.edu/hsr
m/courses/GHSR5301/managerialepi_part2.pptgt
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Cohort Studies Provide Rates

• Incidence Rate, IR, can be calculated by dividing
  the number of adverse events by the number of
  patientyears
• IR dz onsets / ?pt-yrs
• Examples
• Nurses Health Study of 121,000 nurses
• Multiple endpoints

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Prospective Cohort Study--Example

• Source Palareti G et al (2003) Predictive value
  of D-dimer test for recurrent venous
  thromboembolism after anticoagulation withdrawal
  in subjects with a previous idiopathic event and
  in carriers of congenital thrombophilia.
  Circulation 108313-8.
• Cohorts Patients w/ and w/out an elevated
  D-Dimer after standard Rx for a venous
  thromboembolism (VTE).
• Stratified results based on presence or absence
  of genetic thrombophilia, over 1-3 years
• Outcome VTE recurrence
• How would you analyze results?

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Subset with Unprovoked VTE
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Is D-Dimer a Valuable Test?

• D-Dimer is known to be greater in older patients
• Older patients have higher rates of VTE
  recurrence

D-Dimer
New VTE
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Is D-Dimer Confounded by Age?

• D-Dimer is known to be greater in older patients
• Older patients have higher rates of VTE
  recurrence

Age
D-Dimer
New VTE
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Confounding variable is associated with exposure
and a cause of the outcome e.g., cigarette
smoking, coffee drinking and MI Confuses
interpretation of relationship between exposure
and outcome.
Smokes
Coffee
MI
Dr. Jane Garbutt, Sept 10, 2008
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Retrospective Cohort Study--Cohort

• Study Question Does warfarin increase the rate
  of osteoporotic fractures
• Primary outcome Osteoporotic fracture during up
  to 1-year follow-up
• Subjects Medicare beneficiaries with Afib
• Outcome definition ICD-9 code for Fx
• Statistical approach What would you use?

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Results in men (minimal effect in women)
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Results of Cox Proportional Hazards
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Odds Ratio

• Measure strength of association of RF (exposure)
  and outcome with Odds Ratio (OR)
• Disease
• Yes No
• Risk Yes a b
• Factor No c d
• OR odds of exposure in cases a/c
• odds of exposure in controls b/d

Dr. Jane Garbutt, Sept 10, 2008
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Relative Risk

• Disease
• Yes No
• Outcome Risk factor a b ab
• No risk factor c d cd
• ac bd
• RR a/ (ab)
• c/ (cd)
• As formulated here, assumes that the 2 cohorts
  are followed for equal lengths of time.

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Relative and Attributable Risk

• Relative risk (risk ratio) ratio of IR in
  exposed to IR in unexposed
• RR incidence rate among exposed
  (avoids assumption re follow up)
• incidence rate among unexposed
• NB exposure could be a risk factor
• Attributable risk (risk difference) additional
  risk of disease following exposure (i.e. the
  incremental risk above that of the unexposed).
• AR IR among exposed - IR among unexposed

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Risk Reduction

• Relative risk reduction (RRR) is 1 RR
• Absolute risk reduction, ARR
• IRtherapy IRcontrol
• Number needed to treat (NNT)
• number of patients that have to receive the
  therapy to prevent one adverse event
• 1/ARR

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Pros/Cons of Cohort Studies

• Advantages Disadvantages
• Calculation of RR Time consuming
• May yield info. on incidence Require large sample
  sizes
• Clear temporal relationship Expensive
• Can yield info. on multiple Not efficient for
  study of
• outcomes rare events
• Minimizes bias Losses to follow-up
• Strongest observational design
• for establishing cause-effect
• from Greenberg et al.

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Retrospective vs. Prospective

• Attribute Retrospective Prospective
• Information Less complete More complete
• DCd exposures Useful Not useful
• Emerging
• exposures Not useful Useful
• Expense Less costly More costly
• Completion
• time Shorter Longer
• from Greenberg et al.

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Cross-sectional Studies

• Measures prevalence of health outcomes or
  determinants of health (e.g., biomarkers) at a
  point in time or over a short period

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Cross-sectional Studies

• Pros
• Fast (no follow up!)
• Cheap
• Allow for multiple risk factors and outcomes to
  be assessed
• Provide prevalence
• Cons
• Not feasible for rare outcomes
• Temporal association is unclear
• Biases of both exposure and outcome are common
• Does not yield incident rates
• Can identify a cohort that can be followed later
• E.g. Prevalence of non-susceptible S. pneumonia
  to amoxicillin was 3-7 in our community

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Nested Case-Control Study
Source (2 slides) Stanford CLIO
http//clio.stanford.edu7080/cocoon/cliomods/trai
lmaps/design/design/nestedCase-Control/
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Nested Case-Control Study

• Requires a cohort that has been followed over
  time.
• Has exposure information and/or biospecimens
  collected of interest to the investigator.
• Cases incident disease
• Controls Same cohort, but no incident disease
• Compare the exposure frequencies in cases and
  controls as in a non-nested case-control study

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Nested Case-Control Study (2)
Consider the following cohort
X
X case O loss to follow-up
X
O
O
X
t1
t2
t3
Time
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Nested Case-Control Study (3)

• At time t1 the first case occurs for which 8
  eligible controls are identified
• Similarly, there are 5 eligible controls for the
  case at time t2, and 4 eligible controls for the
  case occurring at time t3
• A control can become a case at a later time
  (e.g., cases at t2 and t3 could serve as a
  control for case at t1)
• Controls can be selected randomly from all
  eligible controls (i.e., 1 or more controls for
  each case)
• Number of eligible controls decreases with
  increasing number of matching factors

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Case-Cohort Study (1)
Consider the following hypothetical cohort
X
X case O loss to follow-up
X
O
O
X
t0
Time
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Case-Cohort Study

• In a closed cohort everybody enters cohort at
  start of follow-up t0
• In open cohort the time of entry into the cohort
  is dynamic
• Case-cohort study population consists of all
  cases of any disease of interest, and members of
  the cohort
• A subject might be both case and members of the
  cohort

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Case-Crossover Study

• Study of triggers within an individual
• Case" and "control" component, but information
  of both components will come from the same
  individual
• Case component" hazard period which is the
  time period right before the disease or event
  onset
• Control component" control period which is a
  specified time interval other than the hazard
  period
• Exposure must vary from time to time within
  person
• Disease must have abrupt onset, and effect of
  exposure must be brief
• Examples

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Final Remarks on Cohort and Case-control Studies

• Cohort and case-control studies can be either
  prospective or retrospective, or both
• Prospective Exposure information is collected
  during follow-up, and period of time at risk
  occurs during conduct of the study
• Retrospective Cohorts (cohort study) or cases
  (case-control study) are identified from recorded
  information, and period of time at risk has
  already occurred before the study has begun
• Measures of effect (ratios)
• Cohort study Incidence rate ratio (open cohort)
  or risk ratio (closed cohort)
• Case-control study Exposure odds ratio as
  estimate of incidence rate ratio or risk ratio

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Other Study Designs

• Clinical trials
• randomization of individuals to a treatment or
  reference group
• Intervention studies
• intervention usually on community level rather
  than individual level

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Which Type of Study Design Would You Use

• To evaluate risks and benefits of a therapy
• To evaluate a clinical risk-stratification scheme
  to predict major hemorrhage
• To evaluate the risk of motor vehicle accident
  while talking on a cell phone?
• To evaluate how well genotype (e.g.
  apolipoprotein E2 or E4 allele) predicts
  intracerebral hemorrhage?
• Whether use of the pneumococcal polysaccharide
  vaccine alters the overall risk of
  community-acquired pneumonia
• L Jackson et al. NEJM 3481747-1755 May 2003

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Example Results of WHI
J. Mason Estrogen plus Progestin and the Risk of
Coronary Heart Disease NEJM 349523-534 Aug 2003
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(No Transcript)
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Eg Evaluate a clinical risk-stratification
scheme to predict major hemorrhage
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Gage BF et al. Clinical classification schemes
for predicting hemorrhage. Am Heart J
2006151713-9.
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Redelmeier DA, Tibshirani RJ Association between
cellular-telephone calls motor vehicle
collisions. N Engl J Med 1997 336453-8.
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Next Week

• Endnote, electronic libraries, Wash U Resources
  (Gage)
• Email your protocol outline (2-4 pages
  1.5-spaced) to BGage_at_dom.wustl.edu and
  DWarren_at_im.wustl.edu with this subject line DOC
  Research Protocol Outline ltlast namegt
• Read
• Selby JV et al. A case-control study of
  screening sigmoidoscopy and mortality from
  colorectal cancer. NEJM 1992.
• Hulley chapters 7 9 or Schuster chapters 6, 7.
• Office hours
• Gage Fri, 9/19, 330-500, 3rd floor Wohl,
  Division Clinical Sciences
• Thurs, 9/25 330-430
• Warren Mon, 9/22, 400-500, 15th floor
  Northwest Tower

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Subset w/ Thrombophilia