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## Special Thanks!

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**Bayesian Risk AnalysisWorkshop QuestionsShuji Ogino, M.D.,**Ph.D.AMP Training and Education CommitteeBrigham and Women’s HospitalDana-Farber Cancer InstituteHarvard Medical SchoolI would appreciate any feedbackshuji_ogino@dfci.harvard.edu**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!**Q1. Cystic fibrosis**Non-Hispanic Caucasian family Carrier screening negative for the ACMG 23 mutation panel CF Sensitivity = mutation detection rate = 88% Specificity = 100%**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**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**Q2. Cystic fibrosis testing**Same mutation panel Negative for the same 23 mutation panel Carrier risk? Classic CF patient Tested for the ACMG 23 mutation panel Only one p.F508del detected p.F508del constitutes 72% of all disease alleles**Hints**• Be careful when test result on proband is available • Especially watch for undetectable mutation !**Q3. Tough but common question. Cystic fibrosis testing**Different mutation panels Negative for an expanded mutation panel that detects 93% of Non-Hispanic Caucasian disease alleles Classic CF patient Tested for the ACMG 23 mutation panel (that detects 88% of all disease alleles) Only one p.F508del detected Carrier risk?**Hints**• What is the probability that mutations undetectable by the 23-mutation panel can be detected by the expanded panel?**Q4. Cystic fibrosis testing**Only one detectable mutation (Almost imaginary scenario, but prelude to Q5) Non-Hispanic Caucasian family 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?**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.**Q5. Cystic fibrosis testing**Only one detectable mutation Non-Hispanic Caucasian family Carrier screening shows p.F508del by the ACMG 23 mutation panel 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? Cond. prob. of EB if affected = 0.11 if a carrier = 0.00089 if a non-carrier = 0.00035**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.**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**Q6. 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**Hints**• One comprehensive Bayesian table gives all correct answers at once • Information of a child may modify risks of the parents and grandparents**Q7. Autosomal Dominant Disease**with Age-dependent Penetrance Affected Unaffected at age 50 Heterozygous risk? Disease risk by age 70? Penetrance by age 50 = 0.4 by age 70 = 0.75**Hints**• If he is a carrier, what is the risk to become symptomatic from age 50 to 70?**Q8. Consanguinity: IV-1’s risk for rare AR disease**I-1 I-2 II-1 II-2 II-4 II-3 III-2 III-3 III-1 III-4 IV-1 Carrier IV-2 AR disease V-1**Hints**• Watch for dependent possibilities • Start from a key person (connector between consanguineous couple and proband).**Q9. Isolated Case of X-linked Recessive Disease**Carrier Risk? I-2 II-3 II-4 II-1 II-2 Carrier Risk? Carrier Risk? Age 30, 36 asymptomatic Age 2 months DMD Assume = (same maternal and paternal de novo mutation rate)**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