2013 03 genomic medicine slides

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  • 1. Genes and Environment inPersonalized MedicineAtul Butte, MD, PhDabutte@stanford.eduChief, Division of Systems Medicine,@atulbutte Department of Pediatrics, Department of Medicine, and, by courtesy, Computer ScienceCenter for Pediatric Bioinformatics, LPCHStanford University

2. Disclosures Scientific founder and Honoraria for speaking atadvisory board membership Lilly Genstruct Pfizer NuMedii Siemens Personalis Bristol Myers Squibb Carmenta Speakers bureau None Past or present consultancy Lilly Companies started by students Johnson and Johnson Carmenta Roche Serendipity NuMedii NuMedii Genstruct Stimulomics Tercica NunaHealth Ansh Labs Praedicat Prevendia Flipora Samsung 3. Published online August 10, 20093 4. Lancet, 375:1525, May 1, 2010. 5. Patient zero40 year old male in good health presents to his doctor with his whole genomeNo symptomsExercises regularlyTakes no medicationsFamily history of aortic aneurysmFamily history of sudden deathPresents with 2.8 million SNPs752 copy number variants 6 6. Existing SNP-disease databases are too limitedfor application to a human genome Genome-wide association studies NHGRI GWAS Catalog 1032 papers 5050 SNPs for 557 diseases (6280 records),but 26% without OR, 33% without risk/protective alleles Individual candidate-gene associations NIH Genetic Association Database 56,000 papers, 130,000 records, ~2000 genes, only 4% withdbSNP ids, 1706 with alleles, none with risk/protective Online Mendelian Inheritance in Man Moving to dbSNP ids, monogenic Human Genome Mutation Database 113247 mutations, most Mendelian disease, few SNPs, nogenotypes, or odds ratios 7. Study published in 2008 inInflammatory BowelDisease Crohns Disease andUlcerative Colitis Investigated 9 loci in 700Finnish IBD patients We record 100+ items GWAS, non-GWAS papers Disease, Phenotype Population, Gender Alleles and Genotypes p-value (and confidence) Odds ratio (and confidence) Technology, Study design Genetic modelRong Chen Mapped to UMLS conceptsOptra Systems 8. Study published in 2008 inInflammatory BowelDisease Crohns Disease andUlcerative Colitis Investigated 9 loci in 700Finnish IBD patients We record 100+ items GWAS, non-GWAS papers Disease, Phenotype Population, Gender Alleles and Genotypes p-value (and confidence) Odds ratio (and confidence) Technology, Study design Genetic model Mapped to UMLS concepts 9. Study published in2009 inRheumatology Ankylosingspondylitis Investigated 8SNPs in IL23R in2000 UK case-control patients Tables can be rotated NLP is hard 10. Study published in2009 inRheumatology Ankylosingspondylitis Investigated 8SNPs in IL23R in2000 UK case-control patients Tables can be rotated NLP is hard 11. Study published in2009 inRheumatology Ankylosingspondylitis Investigated 8SNPs in IL23R in2000 UK case-control patients Tables can be rotated NLP is hard 12. What are the alleles for rs1004819? 13. Alleles for rs1004819 are C and T~11% of records reported genotypes in the negative strand 14. VARIMED: Variants Informing Medicine Number ofDistinct Diseases and papers SNPs phenotypes curated ~12,000~192,000 ~4,400Chen R, Davydov EV, Sirota M, Butte AJ.Rong ChenPLoS One. Optra Systems2010 October: 5(10): e13574.Personalis 15. Moving from OR to LROdds ratioRatio of odds of test positivity in cases overodds of test positivity in non-casesLikelihood ratio (+)The probability of test positive in cases, over the probability of test positive in non-casesSensitivity / (1 Specificity)Very similar, but different...Morgan A, Chen R, Butte AJ. Genomic Medicine, 2010. 16. Post-test probability is calculated with likelihood ratioPre-test odds x likelihood ratio Post-test oddsPre-test odds x LR1 x LR2 x LR3 Post-test oddsCan chain likelihood ratios from independent testsMorgan A, Chen R, Butte AJ. Genomic Medicine, 2010. 17. Kohane, Masys, Altman. JAMA 2006, 296:212. 18. Fagan TJ. Nomogram for Bayestheorem. N Engl J Med.1975 Jul 31;293(5): 257.Morgan, Chen, Butte. Likelihoodratios for genomic medicine.Genome Medicine. 2010; 2:30. 19. Fagan TJ. Nomogram for Bayestheorem. N Engl J Med.1975 Jul 31;293(5): 257.Morgan, Chen, Butte. Likelihoodratios for genomic medicine.Genome Medicine. 2010; 2:30. 20. Fagan TJ. Nomogram for Bayestheorem. N Engl J Med.1975 Jul 31;293(5): 257.Morgan, Chen, Butte. Likelihoodratios for genomic medicine.Genome Medicine. 2010; 2:30. 21. Fagan TJ. Nomogram for Bayestheorem. N Engl J Med.1975 Jul 31;293(5): 257.Morgan, Chen, Butte. Likelihoodratios for genomic medicine.Genome Medicine. 2010; 2:30. 22. Current Medical Diagnosisand Treatment, 2007. 23. Current Medical Diagnosisand Treatment, 2007. 24. Current Medical Diagnosisand Treatment, 2007. 25. Rong ChenAlex Morgan Ashley EA*, Butte AJ*,Wheeler MT, Chen R,Klein TE, Dewey FE,Dudley JT, Ormond KE,Pavlovic A, Hudgins L,Gong L, Hodges LM,Berlin DS, Thorn CF,Sangkuhl K, Hebert JM,Woon M, Sagreiya H,Whaley R, Morgan AA, Pushkarev D, Neff NF, Knowles W, Chou M,Thakuria J, RosenbaumA, Zaranek AW, ChurchG, Greely HT*, QuakeSR*, Altman RB*. Clinical evaluationincorporating a personalgenome. Lancet, 2010. 26. Rong ChenAlex Morgan 27. Why do we even have risk alleles? Humans are not a very old species But wouldnt we expect disease risk alleles to beselected against? Disease depends on the environment Sickle cell trait and malaria Cystic fibrosis and cholera Lactase and milk digestion Some risk alleles have positive effects in theright environment So when (and why) might risk alleles haveentered the human genome? 28. Erik CoronaPre-publication, embargoed for press. No tweets please. 29. So what can we do about the risk? Diseases with higher post-test probabilities How to alter the influence of genetics? Diseases are caused by genes and environment We need a simple prescription for environmentalchange for a genome-enabled patient How do we compensate for our genomes? 30. Rong ChenAlex Morgan Joel Dudley 31. How can weexpect physiciansto review6 gigabases ina 15 minuteencounter? 32. We already askphysicians toreview 1 GB ofdata in 15minutes 33. We already askphysicians toreview 1 GB ofdata in 15minutes 34. We already askphysicians toreview 1 GB ofdata in 15minutes but we givethem tools to helpthem do this! 35. Two Major Colliding Directives in Medicine Are Personalized Medicine andQuality Improvement heading onPersonalizeda collision course?Medicine How are we going to treat eachpatient in their own specialway, when we need to treat eachpatient in a standard way?QualityImprovement 36. Data-drivenSystems Medicine 37. Take Home Points Genome-wide sequencing is here: managingthis data and relating to medicineis the challenge. Personalized medicine DNA. Needs toinclude diversity, and other clinical, molecular,and environment measures. Teaching interns, residents, and physicians inall disciplines will be the future rate-limitingchallenge. 38. Funded post-doctoralpositions inTranslationalBioinformaticsavailableFaculty openings fortwo Assistant orAssociateProfessorsContact Atul Butteabutte@stanford.edu 39. Collaborators Jeff Wiser, Patrick Dunn, Mike Atassi / Northrop Grumman Ashley Xia and Quan Chen / NIAID Takashi Kadowaki, Momoko Horikoshi, Kazuo Hara, Hiroshi Ohtsu / U Tokyo Kyoko Toda, Satoru Yamada, Junichiro Irie / Kitasato Univ and Hospital Shiro Maeda / RIKEN Alejandro Sweet-Cordero, Julien Sage / Pediatric Oncology Mark Davis, C. Garrison Fathman / Immunology Russ Altman, Steve Quake / Bioengineering Euan Ashley, Joseph Wu, Tom Quertermous / Cardiology Mike Snyder, Carlos Bustamante, Anne Brunet / Genetics Jay Pasricha / Gastroenterology Rob Tibshirani, Brad Efron / Statistics Hannah Valantine, Kiran Khush/ Cardiology Ken Weinberg / Pediatric Stem Cell Therapeutics Mark Musen, Nigam Shah / National Center for Biomedical Ontology Minnie Sarwal / Nephrology David Miklos / Oncology 40. Support Lucile Packard Foundation for Childrens Health NIH: NIAID, NLM, NIGMS, NCI; NIDDK, NHGRI, NIA, NHLBI, NCATS March of Dimes Hewlett Packard Howard Hughes Medical Institute California Institute for Regenerative Medicine Scleroderma Research Foundation Clayville Research Fund PhRMA Foundation Admin and Tech Staff Stanford Cancer Center, Bio-X Susan Aptekar Rhonda Pisk Alex Skrenchuk Tarangini Deshpande Alan Krensky, Harvey Cohen Hugh OBrodovich Isaac Kohane