EMR 15/QR 50 Medical Detectives

Professor Karin Michels October 1, 2012 Session 4

Marching towards the outcome

Condom Use and HPV Infection

Condom Use and HPV Infection

82 female college students (18-22 years old) Prospective Cohort Study

Condom use No condom use At risk

Winer RL, et al. NEJM 2006;354:2645-54

HPV

No HPV

Winer RL, et al. NEJM 2006;354:2645-54

Thimerosal-Containing Vaccine and Autism

Winer RL, et al. NEJM 2006;354:2645-54

Hviid A, et al. JAMA 2003;290:1763-6

Thimerosal-Containing Vaccine and Autism

All children born in Denmark 1/1/1990 12/31/1996 n=467450

Thimerosal-Containing Vaccine and Autism

Retrospective Cohort Study

Thimerosal-containing vaccine

Autism/Autismspectrum disorder

Thimerosal-free vaccine

No autism

Hviid A, et al. JAMA 2003;290:1763-6

Hviid A, et al. JAMA 2003;290:1763-6

Is there an association between cell phone use and brain cancer?

Cohort Study
Reference Population

Cohort Studies
Study Population

Prospective assessments of exposures and disease outcomes Temporal relation Large in size -> good statistical power Can study many risk factors and many diseases

E E

D D

Not good for the study of rare diseases

Assess and account for many confounders Expensive, lengthy follow-up, loss to follow-up

Cohort Study
Reference Population

2 x 2 Table
Study Population

Disease Exposed Not exposed a c a+c

No disease b d b+d a+b c+d a+b+c+d

E E

D D

Scenario

One Approach: Cohort Study

Sample a group of college students, ask about their iPod habits and follow them over 4 years.

Does regular iPod use increase the risk of hearing loss?

Sample on Exposure

Sample on Exposure
Hearing loss No hearing loss

iPod

2000

iPod

500

1500

2000

No iPod

1000

No iPod

100

900

1000

2 Cumulative Incidences (Absolute Risk)

The risk of developing hearing loss among college students who regularly use iPods is 25% over 4 years (500/2000). The risk of developing hearing loss among those not using iPods is 10% over 4 years (100/1000).

Risk Difference

RD = CI E CI E =
a a+b c c+d

Risk Difference
The difference in the absolute risk of 500 2000 100 1000 developing hearing loss between users of ipods and non-users is 15%.

RD =

= 0.25 0.1 = 0.15

Relative Risk Risk Ratio

Risk of disease in exposed RR = _____________________ Risk of disease in non-exposed a a+b = _________ c c+d
=

Relative Risk Risk Ratio

500 RR = 2000 ________ 100 1000 = 2.5

_________
CI E

CI E

Relative Risk Risk Ratio

Relative to students who do not use iPods, the risk of developing hearing loss is 2.5-fold higher among students who do use iPods

Measures of Association
Measure RD Value 0 Interpretation No association

RR RR RR

1.0 <1.0 >1.0

No association Decreased risk Increased risk

Sample Variability
Reference Population

Random Sample Populations

95% Confidence Intervals

x 1.96 * s.e. (x)

Sample mean

Standard error of sample mean

95% Confidence Intervals for 5 Samples

95% Confidence Interval

Sample 1 5.8 7.5 6.4 8 9.2 9.6 Sample 2 Sample 3 6.8 Sample 4 7.7 6.9 Sample 5

If you take 100 samples from the study population, 95 of the confidence intervals would include the true mean of the reference population

True mean

S.E. and CI for Risk Ratio

SE lnRR =
b d a ( a b ) c (c d )
b d ln RR 1.96 a ( a b ) c (c d )

Measures of Association
Measure RD 95% CI for RD RR Value 0 NOT include 0 1.0 <1.0 >1.0 NOT include 1 Interpretation No association Statistically significant No association Decreased risk Increased risk Statistically significant

95%CI for RR =

RR RR 95% CI for RR

Binomial distribution

Thimerosal-Containing Vaccine and Autism

CI and p-value
95% CI (for RR) p-value Statistically significant Yes

Does not include 1

<0.05

Includes 1

0.05

No

Hviid A, et al. JAMA 2003;290:1763-6

Measurement Error/ Misclassification

What are we measuring ?

Exposure

Outcome

Diet Physical activity Weight Blood pressure

Disease classification (e.g. diabetes, depression) Obesity Blood cholesterol

Misclassification
Always consider BOTH exposure and disease in evaluating misclassification Is the misclassification of exposure the same among people with disease and without? Does the degree of misclassification of the disease differ among the exposed and unexposed? Non-differential

Non-Differential Misclassification of the Disease

D E No E No D E No E D No D

Differential

Misclassification of disease non-differential with respect to exposure

Differential Misclassification of the Disease

D E No E No D E No E D No D

Detection Bias
Misclassification of the disease which is different among the exposed and unexposed Differential misclassification of the disease

Misclassification of disease differential with respect to exposure

Truth
Soda consumption and childhood obesity Obesity Soda No Soda 200 100 300 Not obese 150 150 300 350 250 600

RR = 2.0

Misclassification
Non-differential misclassification may lead to an underestimation of the association

Misclassification of the Disease Non-differential Differential

Obesity Soda No Soda 160 80 240 Not obese 190 170 360 350 250 600 Soda No Soda Obesity 200 50 250 Not obese 150 200 350 350 250 600

Differential misclassification can induce bias in either direction

RR=1.8

RR = 5.3

Key Points Session 4

Cohort study (prospective and retrospective)

Can any of your results be explained by misclassification? Which type?

Study population Element of time, loss-to-follow-up 2x2 table RR calculation Meaning of the CI and p-value Statistical significance

Key Points Session 4

Concept of non-differential misclassification Concept of differential misclassification Effects of misclassification on RR Misclassification and biases