Butte Lab Meeting

July 8, 2015

 

Daniel Himmelstein

Sergio Baranzini Lab

Founding Insight

  • context
    bioinformatics  data explosion
     
  • goal
    mine the data to advance human health
     
  • problem
    high-throughput data tends to predict 
    weakly
     
  • remedy
    combine diverse datasets into a strong predictor
     
  • method
    heterogeneous network edge prediction

Predicting Disease-Associated Genes with Heterogeneous Network Edge Prediciton

In publishing delay at PLOS Computational Biology

wealth of GWAS associations

integrate diverse data to provide context

network of pathogenesis:

 

  • 18 metanodes
  • 40,343 nodes
     
  • 19 metaedges
  • 1,608,168 edges

HNEP

method

classifier:

  • regularized logistic regression
  • glmnet in R
  • mixing parameter
  • top predictions have high lift

mechanisms of pathogenesis:

  • integrative approach is best
     
  • pleiotropy
  • transcriptional signatures of perturbations
  • pathways
  • protein interactions

supplements

Predicting withheld MS associations

Novel MS associations

  • robustness

Network subsampling

Feature redundancy

Metanodes (node types)

Metaedges (edge types)

Drug Repurposing

  • expand our heterogeneous network into the realm of systems pharmacology
     
  • predict indications between
    • approved small molecules
    • complex diseases
    • drug repurposing
       
  • learn the mechanisms of efficacy

17 contributors from 13 institutions

drug repurposing metagraph

Unifying compound vocabularies

  • compounds = DrugBank approved small molecules with structures
  • Compound cannot be reliably matched by names
  • Structures offer a solution
  • Exact matching is limited -- small structural variations
  • UniChem - matches on FIKHB components
  • ThinkLab discussion

Unifying disease vocabularies

  • Disease Ontology (DO)
  • Mappings to other disease terminologies
  • We require terms that are
    • complex diseases
    • distinct
    • of clinically-relevant specificity
    • well annotated in our resources
  • DO Slim

building a catalog of indications

  • gold standard for our supervised approach
     

  • aggregated 4 resources:

    • MEDI-HPS – combines RxNorm, MedlinePlus, SIDER 2, and Wikipedia

    • ehrlink – linked data from health records

    • LabeledIn – expert and MTurk curated drug labels

    • PREDICT – UMLS links, drugs.com, drug labels
       

  • 1,388 high and 1,114 low-confidence indications

Side Effects

  • drug targets are poorly characterized
     
  • embrace polypharmacology
     
  • side effects may indicate unknown off-targets
     
  • high-throughput methods
    • drug labels (SIDER 2)
    • FDA AERS (OFFSIDES)
    • text mining

LINCS L1000

  • Library of Integrated Cellular Signatures
     
  • L1000 - Transcriptional profiles
    • ~20,000 small molecules
    • 978 measured genes
       
  • Leo Brueggeman
     
  • Resources
    • http://slides.com/leoo/lincs#/
    • https://dx.doi.org/10.6084/m9.figshare.1476293
    • http://thinklab.com/d/43

L1000 workflow

We combine all signatures for each DrugBank compound to get a consensus signature

Disease-specific models uncover therapeutic signatures

Mining MEDLINE

http://thinklab.com/d/67

  • curators read abstracts and annotate topics
     
  • 21 million articles
  • 5,594 journals
     
  • cooccurence of two topics indicates a relation

anatomy

symptom

Mining MEDLINE for disease context

Tissue-specific expression

  • Bgee
    curates microarray and RNA-Seq experiments 
    http://bgee.unil.ch/

  • TISSUES
    transcriptomics, proteomics, text mining, UniProtKB
    http://tissues.jensenlab.org/About

http://thinklab.com/d/81

number of transcribed genes: developmental stage × anatomy

http://thinklab.com/d/81#293

Number of enriched and depleted genes by anatomy 

http://thinklab.com/d/81#293

  • depletion is more common than enrichment
     

  • highly-specialized tissues have the greatest differential expression

Next steps

  • transcriptional signatures of disease (STAR-GEO)
     
  • improved side effect resource
     
  • removal of symptomatic indications
     
  • discoveries!

Questions & Suggestions

Butte Lab Meeting

By Daniel Himmelstein

Butte Lab Meeting

Presentation to the Atul Butte group at UCSF on July 8, 2015

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