2018/4/21 Disclosures Precision Medicine Approaches for Studying Preterm Birth: The Role of Big Data • Currently scientific advisor at T woXAR • Shareholder in Somnics • Previously a Consultant at RevMed, NGM Pharmaceuticals and Novartis • Previously employed at Pfizer • Invited talks at Genentech, Novartis, 23andme, DNANexus, Sirota Lab Lifecode, RevMed, Circuit Therapeutics Marina Sirota, PhD Assistant Professor Why Now? Moore’s Law – Biology and Computation Cost Per Genome Cost of Computational Resources 1
2018/4/21 Integrative Personal “Omics” Profiling Transcriptome Genome Epigenome Antibodyome Microbiome Proteome / Metabolome Pregnancy and Preterm Birth Why Study Preterm Birth? Preterm birth (PTB) - live birth before week 37 of gestation 2nd trimester 3rd trimester 1st trimester (T1) (T2) (T3) Worldwide, 15 million babies are born premature each year. One million of these infants die within the first 28 days of life. In nearly half of the cases of premature birth, there is no clear cause. 2
2018/4/21 Integrative Computational Approaches for Integrative Computational Approaches for Preterm Birth Research Preterm Birth Research • Elucidating Genetic and Environmental Determinants of • Elucidating Genetic and Environmental Determinants of Preterm Birth Preterm Birth • Nadav Rappoport, Aolin Wang, Hongtai Huang • Nadav Rappoport, Aolin Wang, Hongtai Huang • Microbiome Meta-Analysis in Preterm Birth • Microbiome Meta-Analysis in Preterm Birth • Idit Kosti • Idit Kosti • Transcriptomic Meta-Analysis in Preterm Birth • Transcriptomic Meta-Analysis in Preterm Birth • Bianca Vora and Aolin Wang • Bianca Vora and Aolin Wang • Integrating Clinical and Molecular Measurements to Study • Integrating Clinical and Molecular Measurements to Study Preterm Birth Preterm Birth • Carolyn Wang, Brian Le and Idit Kosti • Carolyn Wang, Brian Le and Idit Kosti Evidence for the Genetic Component Genome-wide Association Study Identifies Ancestry Specific Variants Associated with to Preterm Birth Spontaneous Preterm Birth • Both preterm and postterm births tend to recur in mothers • Birth timing trends among family members Nadav Rappoport* , Jonathan Toung * , Dexter Hadley, Ron Wong, Kazumichi Fujioka, • T win studies estimate that ~30% of variation in preterm Jason Reuter, Charles W Abbott, Sam Oh, Donglei Hu, Celeste Eng, Scott Huntsman, birth is genetic Dale L Bodian, John E Niederhuber, Xiumei Hong, Ge Zhang, Weronika Sikora- • Racial disparities in preterm birth Wohfeld, Christopher R. Gignoux, Hui Wang, John Oehlert, Laura Jelliffe, Jeffrey • Large studies carried out on the maternal side, not much on Gould, Gary Darmstadt, Xiaobin Wang, Carlos Bustamante, Esteban Burchard, the fetal genetics to date Michael Snyder, Elad Ziv, Nikolaos A Patsopoulos, Louis J Muglia, Gary M. Shaw, Hugh M. O'Brodovich, David K. Stevenson, Atul J. Butte*, Marina Sirota* Plunkett and Muglia 2008, Zhang 2017 Scientific Reports, 2018 3
2018/4/21 Integrating Genetic Data Key Insight • Cases: 1726 PTB individuals* • Premature babies are at risk of respiratory distress syndrome (RDS) because their immature lungs do not produce enough surfactant, a – 900 Male; 826 Female protein that keeps small air sacs in lungs from collapsing – Genomic DNA extracted from newborn screening bloodspots • March of Dimes helped develop surfactant therapy, which was – Illumina Human Omni 2.5 introduced in 1990 • Controls: • Prior to 1990, babies born between 24-28 weeks gestation were highly unlikely to survive and thus are likely underrepresented in – Health and Retirement Study (HRS) is a longitudinal study with genotyping for over the adults over 25 years of age age of 50, ~10K individuals – Illumina Human Omni 2.5 HRS participants (55-80+ year olds) can serve as controls against the • Population Mapping – 1,000 Genomes PTB cohort * Wang et al, 2013 Extreme Preterm Birth (PTB) Cases < 30 Weeks Health and Retirement Genetic Associations with PTB in the AMR Cohort Study (HRS) Controls (12,570 Individuals) Spontaneous PTB (1349 Individuals) Use 1000 Genomes to map populations Americas (AMR) African (AFR) European (EUR) South Asian (SAS) East Asian (EAS) Population-Specific Case Control Analysis Nadav Rappoport, PhD 4
2018/4/21 Genetic Associations with PTB in the AMR Cohort Plotted SNPs 10 r 2 0.8 0.6 8 rs1979081 0.4 0.2 - log 10 (p−value) 6 4 2 0 OR4F21 FAM87A TDRP ERICH1 RPL23AP53 FBXO25 ERICH1−AS1 ZNF596 0 0.2 0.4 0.6 0.8 Position on chr8 (Mb) Hongtai Huang, Amy Padula, Tracey Woodruff, PTBi Nadav Rappoport, PhD Version 3.0 Database Inpatient Discharge Data • 37 Exposure Indicator Variables • Year 2009-2012 • 8,035 Census Tracts • Preterm Birth Prevalence: 6.84% • 58 Counties • 6,503 Census Tracts with ID labels Initial Matching Strategy Exact Match by Census Tract Information (40% Matched) N=1,812,145 Match by Census Tract based on Secondary Matching Strategy Area Weighting Method (74% Matched) Match by Census ZIP Code ZIP Code Interpolation Method Tabulation Area N=1,797,284 (99% Matched) Hongtai Huang (Submitted) Hongtai Huang, Amy Padula, Tracey Woodruff, PTBi 5
2018/4/21 Integrative Computational Approaches for Preterm Birth Research • Elucidating Genetic and Environmental Determinants of Preterm Birth • Nadav Rappoport, Aolin Wang, Hongtai Huang • Microbiome Meta-Analysis in Preterm Birth • Idit Kosti • Transcriptomic Meta-Analysis in Preterm Birth • Bianca Vora and Aolin Wang • Integrating Clinical and Molecular Measurements to Study Preterm Birth • Carolyn Wang, Brian Le and Idit Kosti Hongtai Huang (Submitted) Microbiome Meta-Analysis: Challenges and Public Pregnancy Microbiome Data Opportunities # of # of Mother/ # of # of Type of body Species # of reads Reference Body sites Time points • Impossible to combine processed data, need to go back to the samples Baby Subjects Data sites The Human raw data Mouth, Nose, Microbiome HMP 5,298 Controls 242 18 5385 30,336,944 Skin, Gut and 16s Controls Project Vagina • Sample metadata is hard to get access to Consortium Stanford PTB Vagina, Gut, 16s, Longitudinal 4,399 Mother 51 11 4694 656,308 DiGiulio et al. Saliva, and Weekly • Lots of potential biases: WGS (MOD) Tooth/Gum Placenta Penn 69 Mother 6 5 2108 207,5881 Lauder et al. Placenta, Vagina 16s Delivery – 16s vs. whole genome Every 4 weeks until 24, Vaginal PTB 349 Mother 100 1 550 2,213,608 Romero et al. Vagina 16s every 2 weeks until the – Taxa vs. gene analysis last prenatal visit – Sample prep differences Placenta PTB 48 Mother 48 1 TBD 1,348,416 Aagard et al. Placenta 16s, WGS Delivery Gut – Variable regions of the 16s Mother/ Microbiome in 972 91 1 2339 112,8572 Koren et al. Gut 16s T1,T3,PP Baby Pregnancy gene that were sequenced Vaginal MacIntyre et TBD Mother 42 1 TBD TBD Vagina 16s T1,T2,T3,PP Pregnancy al. – Longitudinal vs. Case-Control Stephen Nayfach and Katie Pollard, 2016 6
2018/4/21 Microbiome Meta-Analysis Across Body Sites Microbiome Meta-Analysis Pipeline Is time consuming and computationally intensive >10,000 samples 12,427s of OTUs Raw Reads, Metadata Raw Reads ~1000 OTUs post Study Name Size filtering HMP 19.03GB UPARSE (Trimming, Clustering, Aligning) Stanford PTB Longitudinal 8.98GB UPARSE (Assign Taxonomy) (MOD) Placenta Penn 991.2MB Vaginal PTB 1.28GB Operational Taxonomical Unit (OTU) Tables Placenta PTB 490.9MB Gut Microbiome 427.2MB Statistical Analysis in Pregnancy PRELIMINARY Idit Kosti, PhD Idit Kosti, PhD Bacterial Vaginosis is a Known Risk Factor for PTB • Bacterial vaginosis is a state of an overgrowth of anaerobic bacteria, replacing the normal vaginal Lactobacillus. Can we identify new microbial species associated • Bacterial vaginosis has been shown to increase the risk for with PTB in a longitudinal analysis leveraging preterm birth. public data? • Several microbiome studies have been carried out but no meta-analysis to date. Manns-James L., J Midwifery Womens Health, 2011 7
Recommend
More recommend
