Bayesian Risk Analysis Workshop Quiz Shuji Ogino, M.D., Ph.D. Associate Professor of Pathology Harva

1
Bayesian Risk AnalysisWorkshop QuizShuji
Ogino, M.D., Ph.D.Associate Professor of
PathologyHarvard Medical SchoolBrigham and
Womens HospitalDana-Farber Cancer InstituteI
have no conflict of interest
2
Special Thanks!

• Mary Lowery-Nordberg and Hanna Rennert AMP
  Genetics Subdivision
• Jennifer Hunt AMP Training and Education
  Committee
• Jeff Kant and Tim OLeary AMP Program Committee
• Rob Wilson, Pam Flodman, Pam Hawley, Bert Gold
  and Wayne Grody collaborators of risk analysis
  projects
• Early-birds, thank you!

3
References

• Young. Introduction to Risk Calculations in
  Genetic Counseling. Oxford Univ Press 2007.
• Very comprehensive book
• Ogino and Wilson. Bayesian Analysis and Risk
  Assessment in Genetic Testing and Counseling. J
  Mol Diagn 2004 6 1-9.
• Succinct introduction for free downloading

4
Take home this message

• Assuming is a key to success in Bayesian analysis

5
Q1. Cystic fibrosis Non-Hispanic
Caucasian family
Classic CF
Carrier screening negative for the ACMG 23
mutation panel What is her carrier probability?
Sensitivity mutation detection rate
90 Specificity 100
6
Hints

• Sensitivity carriers with positive results /
  all carriers (or patients)
• you want them to be all positive
• Specificity non-carriers with negative results
  / all non-carriers (or controls)
• you want them to be all negative

7
Sensitivity A / (A B) Specificity D / (C
D)
8
Carrier
Non-carrier
False positive Abnormal test C
Sensitivity
True positive A
True negative D
specificity
False negative Normal test B
1 - sensitivity
9
Q2. Autosomal Dominant Disease with Imcomplete
Penetrance
Affected
Unaffected at age 50 Carrier risk?
Penetrance at age 50 0.4
10
Q3. Autosomal Dominant Disease with
Age-Dependent Penetrance
Affected
Unaffected at age 50 Disease risk by age 70?
Penetrance by age 50 0.4 by age 70
0.8
11
Affected
Assume he is heterozygous
Penetrance by age 50 0.4 by age 70
0.8
0.4
0.6
Age 50
Unaffected
Affected
0.8
Age 70
Affected
0.4
Affected
Assuming he is heterozygous and unaffected at age
50, disease probability by age 70 0.4 / 0.6
2/3
12
Q4. Isolated Case of X-linked Recessive Disease
Carrier risk?
Lethal XR Disease
Assume ? ?
13
Isolated Case of Lethal X-linked Recessive
Disease
Carrier risk 2/3
Assume ? ? (maternal paternal de novo
mutation rates)
Lethal XR Disease
14
Q5. X-linked Recessive Disease
DMD
CPK abnormal 2 sons unaffected Carrier risk?
DMD
Unaffected 10y 8y
Sensitivity of CPK test (to detect carriers)
2/3 Specificity 0.95 (19/20)
15
Q6. Cystic fibrosis testing Same mutation panel
Negative for the same 23 mutation panel
What is her carrier risk?
Classic CF patient Tested for the ACMG 23
mutation panel Only one p.F508del p.F508del
constitutes 72 of all disease alleles Does it
matter whether the mutation in the proband is
p.F508del or any of the other 22 mutations?
16
Non-carrier 1/2
Carrier 1/2
Prior probabilities

1/2

1/4 Carrier p.F508del
1/4 Undetectable
Carrier screening negative
Carrier risk?
17

• Advanced Risk Analysis
• Very Practical, Challenging Cases
• Board exam takers, dont worry!!!
• You will not see these in exams

18
Q7. Cystic fibrosis testing Different mutation
panels
Negative for an expanded mutation panel that
detects 93 of Non-Hispanic Caucasian disease
alleles
non-Hispanic Caucasian patient with classic
CF Tested for the ACMG 23 mutation panel (that
detects 90 of all disease alleles) Only one
p.F508del detected
What is her carrier risk?
19
Non-carrier 1/2
Carrier 1/2
Prior probabilities

1/2

1/4 Carrier p.F508del
1/4 Undetectable
Carrier screening negative
Carrier risk?
20
HintWhat is the detection rate of the extended
panel, when tested for the non-23 mutations?
21
Q8. Autosomal Dominant Disease
Affected
Unaffected. Carrier risk?
II-2
Age 65
Unaffected. Carrier risk?
III-1
Penetrance at age 65 0.6 at
age 40 0.3
Age 40
22
How about stepwise answer?
This can give the right answer for III-1, but
this does NOT give correct II-2s risk, because
information on III-1 (no symptom) influences the
risk of II-2
23
Q9. Cystic fibrosis testing Only one detectable
mutation
Non-Hispanic Caucasian family
Only one p.F508del by Prenatal CFTR testing with
ACMG 23 mutation panel (that detects 90 of
disease alleles). p.F508del constitutes 72 of
all disease alleles To simplify, no other risk
factor exists What is CF disease risk?
24

Non-Hispanic Caucasian family. No family history
of CF
Prior probabilities CF 1/2500 0.0004 Carrier
1/25 0.04 Non-carrier 24/25 0.96