Pharmacogenetics

1
More on Study Designs Brian F. Gage, MD,
MSc Department of General Medical Sciences
Associate Professor of Medicine September 24,
2008
2
Submit your Protocols

• Protocols have been good
• Remember to define every abbreviation
• Reviewers may not be in your field
• Then, use the abbreviation!
• Be consistent w/ terminology order
• dose revision dose refinement dose
  adjustment?
• drug induction drug initiation ?

3
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
4
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
5
Case-Control Studies
Study Onset
Time
Exposed
Cases
Unexposed
Exposed
Controls
Unexposed
Direction of Inquiry
6
Nested Case-Control Study
Source (2 slides) Stanford CLIO
http//clio.stanford.edu7080/cocoon/cliomods/trai
lmaps/design/design/nestedCase-Control/
7
What If We Study Cases and Compare them to
Population?

• Sequence of the Fibrillin-1 gene analysis gene in
  patients w/ Marfans syndrome
• We would find a high prevalence of certain
  variants in cases w/ Marfans
• We could compare the prevalence of these variants
  to the overall prevalence in the general
  population (matched for race).
• Not controls because someone in the population
  cohort might have Marfans

8
Case-Cohort Studies(This term is also used when
following cases)
Study Onset
Time
Exposed
Cases
Unexposed
Exposed
Cohort
Unexposed
May include rare cases
Direction of Inquiry
9
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

10
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

11
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

12
Intro to Hazard Ratios 95 CI

• Hazard ratio The hazard ratio describes the
  relative risk of the outcome based on
  time-to-event analysis.
• 95 CI Theoretical distribution of a parameter
  whereby 95 of repeated, identical studies would
  fall.

13
Example What is the RR of CHD in Womens Health
Initiative (WHI)?
J. Mason Estrogen plus Progestin and the Risk of
Coronary Heart Disease NEJM 349523-534 Aug 2003
14
(No Transcript)
15
How Would We Determine Whether Screening Flex Sig
Prevents Distal Colon CA?

• Subjects
• Study Design (besides an RCT)
• Outcome
• Assessment of Causal Relationship?

16
How Would We Determine Whether a Low Salt (or Low
Sugar) Diet Lowered B.P.

• Subjects
• Study Design (besides an RCT)
• Outcome
• Strength of Causal Relationship?

17
How Would We Determine Whether Folic Acid
Supplementation Prevent Neural Tube Defects

• Subjects
• Study Design
• Outcome
• Assessment of Causal Relationship?