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Translational Case Histories Harvard Medical School Center for Biomedical Informatics i2b2 National Center for Biomedical Computing i2b2 Informatics for Integrating Biology & the Bedside Isaac S. Kohane, MD, PhD John Glaser, PhD Susanne Churchill, PhD A National Center for Biomedical Computing i2b2 Informatics for Integrating Biology & the Bedside A National Center for Biomedical Computing i2b2 Informatics for Integrating Biology & the Bedside First signal: • 1 year after Celecoxib • 8 months after Rofecoxib A National Center for Biomedical Computing i2b2 Informatics for Integrating Biology & the Bedside • For every million prescriptions, 0.5% increase in MI (95%CI 0.1 to 0.9) • 50.3% of the deviance explained A National Center for Biomedical Computing Effect on patient age i2b2 Informatics for Integrating Biology & the Bedside • Negative association between mean age at MI and prescription volume • Spearman correlation -0.67, P<0.05 A National Center for Biomedical Computing I2B2: Test RelNet Project Correlate available GEO expression data for GPL96 platform containing expressions for more than 22K human genes Number of gene pairs for this gene chip: ~ 250 Million Multi-threaded application to run on the high-performance Cluster environment from HP Bottleneck: the back-end Database Current, fine-tuned version of the application takes about 2-3 months to complete one data set calculation i2b2 Informatics for Integrating Biology & the Bedside A National Center for Biomedical Computing i2b2 Informatics for Integrating Biology & the Bedside A National Center for Biomedical Computing i2b2 Informatics for Integrating Biology & the Bedside A National Center for Biomedical Computing Average BMI by Age 35 Obesity 34 33.5 33 32.5 32 31.5 31 Distribution of Highest BMI of each Patient 30.5 i2b2 Informatics for Integrating Biology & the Bedside 78 10000 75 72 69 66 63 60 57 54 51 48 Age 9000 8000 7000 Total Patients 6000 5000 4000 3000 2000 1000 BMI A National Center for Biomedical Computing 89 82 78 74 70 66 62 58 54 50 46 42 38 34 0 30 45 42 39 36 33 30 27 24 21 30 18 Average BMI 34.5 Recurrent Themes • Access to large numbers of phenotyped specimens • Inadequacy of informatics at the cutting edge – Inadequacy of software solutions alone • A persistent multidisciplinary requirement i2b2 Informatics for Integrating Biology & the Bedside A National Center for Biomedical Computing i2b2 Overall Remission Rate with Citalopram QIDS: Quick= Inventory of Depressive Symptoms, self report 32.9% Percent (%) N = 943/2876 No Mild Moderate Severe depression symptoms symptoms symptoms Last QIDS-SR Score Trivedi MH, et al. Am J Psychiatry 2006;163:28-40. Informatics for Integrating Biology & the Bedside A National Center for Biomedical Computing Very severe symptoms Aims: • Identify a cohort of patients with TRD, and a matched cohort with SSRI-responsive MDD. – Data-mining tools – Natural language processing • Conduct the first genomewide association study of TRD. i2b2 Informatics for Integrating Biology & the Bedside A National Center for Biomedical Computing i2b2 Informatics for Integrating Biology & the Bedside A National Center for Biomedical Computing • Scan computerized medical records (DataMart) – ICD9 RA x 3 plus one of: • CCP or RF • Erosions on x-ray adds >95% specificity • DMARD treatment • Crimson “discarded” blood samples (cases and controls) • CCP on all samples (and bank serum) • DNA on all samples for genetic studies i2b2 Informatics for Integrating Biology & the Bedside www.i2b2.org/disease/arthritis.html A National Center for Biomedical Computing i2b2 Informatics for Integrating Biology & the Bedside A National Center for Biomedical Computing i2b2 Association in population samples Affecteds Controls SNP frequency in cases compared to controls Positive controls: MHC, PTPN22, STAT4, TRAF1-C5, TNFAIP3 Informatics for Integrating Biology & the Bedside A National Center for Biomedical Computing cgt…ggaatac…... cgt…ggaatac….. …...a Allele ‘A’ NspI …...a NspI NspI cgt…ggattac….. cgt…ggattac…… …...a Allele ‘B’ NspI NspI ......a NspI NspI NspI MSRE digested Allele ‘A’ Allele ‘B’ AB control (no digestion) i2b2 Informatics for Integrating Biology & the Bedside A_ _B ‘A’ methylated ‘B’ methylated ‘B’ expressed ‘A’ expressed A National Center for Biomedical Computing __ both unmethylated both expressed Methodology Dev i2b2 Informatics for Integrating Biology & the Bedside A National Center for Biomedical Computing Making the numbers better i2b2 Informatics for Integrating Biology & the Bedside A National Center for Biomedical Computing Gene Network Enrichment Analysis Microarray data Protein protein interaction network i2b2 Informatics for Integrating Biology & the Bedside Biological Process A National Center for Biomedical Computing Molecular Function Diabetes Genome Anatomy Project: Mouse Models of Insulin Resistance, Insulin Deficiency and Obesity • Knockouts – – – – Insulin receptor Insulin receptor substrates Leptin PGC1A • Environmental – High fat diets – Drug treatments (Streptozotocin) 67 Conditions Total i2b2 Informatics for Integrating Biology & the Bedside A National Center for Biomedical Computing Tissues Three Functional Sets Are Consistently Over-represented In Disease Models 1. Insulin signaling, interleukins, and nuclear receptors. 2. Insulin signaling is consistent with the given disease models. Was not identified using standard techniques. 3. Interleukins and nuclear receptors consistent with the inflammation and disordered metabolism associated with type 2 diabetes. i2b2 Informatics for Integrating Biology & the Bedside Insulin signaling Nuclear Receptors Nuclear receptors: 31 of 67. Interleukins: 38 of 67. Insulin signaling: 45 of 67. A National Center for Biomedical Computing Interleukins Early evidence of signature from WBC i2b2 Informatics for Integrating Biology & the Bedside A National Center for Biomedical Computing Predicting CAG Length in HD i2b2 Informatics for Integrating Biology & the Bedside QuickTime™ and a decompressor are needed to see this picture. A National Center for Biomedical Computing i2b2 Informatics for Integrating Biology & the Bedside Thank you A National Center for Biomedical Computing