1. Bayesian Risk Analysis Workshop Questions Shuji Ogino, M.D., Ph.D. AMP Training and Education Committee Brigham and Women’s Hospital Dana-Farber Cancer Institute Harvard Medical School I would appreciate any feedback shuji_ogino@dfci.harvard.edu

2. Special Thanks! Rob Wilson, Pam Flodman, Pam Hawley, Bert Gold and Wayne Grody; collaborators of risk analysis projects Jean Amos Wilson, Vicky Pratt and Ed Highsmith; helpful suggestions AMP Program Committee, Training and Education Committee, and Genetics Subdivision Early-birds, thank you!

3. CF Carrier screening negative for the ACMG 23 mutation panel Q1. Cystic fibrosis Non-Hispanic Caucasian family Sensitivity = mutation detection rate = 88% Specificity = 100%

4. Hints Sensitivity = positive / all carriers (or patients); you want them to be positive Specificity = negative / all non-carriers (or controls); you want them to be negative

5. Hints For alternative possibilities (e.g., carrier vs. non-carrier), always assume one of them is true (e.g., she is a carrier), then calculate the probability that the test result (negative) happens (= conditional probability) Assuming = key to success in Bayes

6. Classic CF patient Tested for the ACMG 23 mutation panel Only one p.F508del detected p.F508del constitutes 72% of all disease alleles Negative for the same 23 mutation panel Carrier risk? Q2. Cystic fibrosis testing Same mutation panel

7. Hints Be careful when test result on proband is available Especially watch for undetectable mutation !

8. Classic CF patient Tested for the ACMG 23 mutation panel (that detects 88% of all disease alleles) Only one p.F508del detected Negative for an expanded mutation panel that detects 93% of Non-Hispanic Caucasian disease alleles Carrier risk? Q3. Tough but common question. Cystic fibrosis testing Different mutation panels

9. Hints What is the probability that mutations undetectable by the 23-mutation panel can be detected by the expanded panel?

10. Only one p.F508del detected by prenatal testing with ACMG 23-panel (that detects 88% of disease alleles). p.F508del constitutes 72% of all disease alleles What is CF disease risk? Non-Hispanic Caucasian family Q4. Cystic fibrosis testing Only one detectable mutation (Almost imaginary scenario, but prelude to Q5)

11. Hints Assume AFFECTED fetus, then calculate conditional probabilities Assume CARRIER fetus, then calculate conditional probabilities Assume NON-CARRIER fetus, then calculate conditional probabilities For further reading: Ogino et al. J Med Genet 2004;41:e70.

12. Fetal echogenic bowel (EB)+ Only one p.F508del by prenatal testing (ACMG 23 mutation panel that detects 88% of disease alleles). p.F508del = 72% of all mutant alleles What is CF disease risk? Non-Hispanic Caucasian family Q5. Cystic fibrosis testing Only one detectable mutation Carrier screening shows p.F508del by the ACMG 23 mutation panel Cond. prob. of EB if affected = 0.11 if a carrier = 0.00089 if a non-carrier = 0.00035

13. Hints Start Bayesian analysis from the top Assume carrier father, then calculate conditional probabilities Assume non-carrier father, then calculate conditional probabilities –For further reading: Ogino et al. J Med Genet 2004;41:e70.

14. From here: Advanced questions for other diseases Three reasons to do: 1. You can have fun in an airplane to the meeting 2. We can go over if time allows at the workshop (answers will be available) 3. I am always happy to discuss

15. Q6. Autosomal Dominant Disease III-1 Affected Age 65 Age 40 Penetrance at age 65 = 0.6 at age 40 = 0.3 Unaffected. Carrier risk? Unaffected. Carrier risk? II-2

16. Hints One comprehensive Bayesian table gives all correct answers at once Information of a child may modify risks of the parents and grandparents

17. Unaffected at age 50 Heterozygous risk? Disease risk by age 70? Penetrance by age 50 = 0.4 by age 70 = 0.75 Q7. Autosomal Dominant Disease with Age-dependent Penetrance Affected

18. Hints If he is a carrier, what is the risk to become symptomatic from age 50 to 70?

19. I-1I-2 II-1II-2 II-3 II-4 III-1 III-2III-3 III-4 IV-1 IV-2 Q8. Consanguinity: IV-1’s risk for rare AR disease AR disease V-1 Carrier

20. Hints Watch for dependent possibilities Start from a key person (connector between consanguineous couple and proband).

21. DMD Assume  = (same maternal and paternal de novo mutation rate) Age 2 months Age 30, 36 asymptomatic Q9. Isolated Case of X-linked Recessive Disease Carrier Risk? I-2 II-3II-4 II-2 Carrier Risk? II-1 Carrier Risk?

22. Hints Start analysis from the top One comprehensive Bayesian table can give all answers at once Carrier risk = 4  (given  = ) for a woman with no relative affected with lethal X-liked recessive disease