Translational Bioinformatics 2013: The Year in Review

Russ B. Altman, MD, PhD Stanford University

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Disclosures
Founder & Consultant, Personalis Inc (genome
sequencing for clinical applications). NextBio, Novartis.

Consultant current or recently: 23andme, Funding support: NIH, NSF, Microsoft, Oracle,
Lightspeed Ventures, PARSA Foundation. clinical pharmacology.

I am a fan of informatics, genomics, medicine &

Goals
Provide an overview of the scientic trends Create a snapshot of what seems to be Marvel at the progress made and the
opportunities ahead. and publications in translational bioinformatics important in March, 2013 for the amusement of future generations.

Process
1. Follow literature through the year 2. Solicit nominations from colleagues 3. Search key journals and key topics on PubMed 4. Stress out a bit. 5. Select papers to highlight in ~2-3 slides

 Translational bioinformatics = informatics Considered last ~14 months (to this week) Focused on human biology and clinical NOTE: Amazing biological papers with

Caveats

methods that link biological entities (genes, proteins, small molecules) to clinical entities (diseases, symptoms, drugs)--or vice versa.

implications: molecules, clinical data, informatics. straightforward informatics generally not included. link clinical to molecular generally not included.

NOTE: Amazing informatics papers which dont

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Final list
350 Quarter nalists, 242 Semi nalists, 98 nalists 27 Presented here (briey) + 10 shout outs Apologies to those I misjudged. Mistakes are mine. This talk and bibliography will be made available on
the conference website and my blog on rbaltman.wordpress.com drugs, delivery.

TOPICS: Omics medicine, cool methods, cancer,

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Thanks!
Darrell Abernethy Andrea Califano Josh Denny Joel Dudley Mark Gerstein George Hripcsak Konrad
Karczewski

Isaac Kohane Lang Li Yong Li Tianyun Liu Yves Lussier Dan Masys Hua FanMinogue Alex Morgan Sandy Napel

Lucila OhnoMachado Raul Rabadan Dan Roden Nigam Shah David States Nick Tatonetti Jessie
Tenenbaum

Omics Medicine

The predictive capacity of personal genome sequencing. (Roberts et al, Science TM)

Goal: Estimate the maximum capacity of genome

to identify clinical risk for disease. disease co-occurrence statistics.

Method: Estimate clinical risk based on identical twin Result: For 23/24 most individuals negative, but for
19 diseases still signicant risk. 90% of individuals alerted to at least one increased risk. individuals.

Conclusion: Limited value of genomics to

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Min/Max % of population test positive

Min/Max RR of disease after testing negative

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Comparison of family history and SNPs for predicting risk of complex disease. (Do et al, PLOS Genetics)

Goal: Understand relative value of family history

versus common SNPs. SNPs.

Method: Compare risk assessment using FHx and Result: Family history most useful for common
commonly assumed in terms of clinical utility. disease and roughly equivalent to SNPs. SNPs more useful for rare disease (<4%).

Conclusion: Genetics may be doing better than

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Disease more genetic

Disease more common

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Diverse types of genetic variation converge on functional gene networks involved in schizophrenia. (Gilman et al, Nature Neuro)

Goal: Dene the underlying molecular mechanisms

of schizophrenia.

Method: Integrated analysis of disease-related

genetic data (CNVs, SNVs, GWAS associations). expressed in brain, especially prenatally. Pathways related, but mutations different from those seen in autism.

Result: Several cohesive networks identied. Genes Conclusion: Schizophrenia may begin to yield...
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Tracking a hospital outbreak of carbapenemresistant Klebsiella pneumoniae with whole-genome sequencing. (Snitkin et al, Science TM)

Goal: Use whole-genome sequencing to track

epidemiology of deadly resistant bacteria. reconstruct outbreak dynamics.

Method: Integrate genomics & epidemiology to Result: Index patient transmitted to 3 others & was
discharged 3 weeks before next case!

Conclusion: Genomics is powerful tool for

outbreak monitoring and reconstruction.
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Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. (Voight et al, Lancet)

Goal: Assess whether HDL is causal for reducing

risk of MI or simply biomarker.

Method: Find genetic variants that raise HDL, and

see if they also reduce risk of MI. (Control: LDL)

Result: LDL is causal. HDL...not so much. Conclusion: Genetics provides a window for not

only discovering biomarkers but validating them as causal or not.

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Shout outs
Goal: Explain why genetic associations seem to leave so much heritability unexplained. The mystery of missing heritability: Genetic interactions create phantom heritability. (Zuk et al, PNAS) Estimating genetic effects and quantifying missing heritability explained by identied rare-variant associations. (Liu & Leal, Amer J Hum Gen)

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Other shout outs...

Identication of risk loci with shared effects on ve major psychiatric disorders: a genome-wide analysis. Cross-Disorder Group of the Psychiatric Genomics Consortium, Lancet An integrated map of genetic variation from 1,092 human genomes The 1000 Genomes Project Consortium, Nature An integrated encyclopedia of DNA elements in the human genome. ENCODE Project Consortium, Nature Architecture of the human regulatory network derived from ENCODE data. Gerstein et al, Nature Personal omics proling reveals dynamic molecular and medical phenotypes.. Chen et al, Cell Systematic localization of common disease-associated variation in regulatory DNA. Maurano et al, Science
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Cool methods

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Bayesian ontology querying for accurate and noisetolerant semantic searches. (Bauer et al, Bioinformatics)

Goal: Support semantic search over disease

phenotypes tolerant to noise in data & input networks to infer diseases from input phenotypes

Method: Combine ontological analysis and Bayesian Result: Improved search performance (ROC) Conclusion: Bayesian reasoning on ontologies can
smooth them and make inference more tolerant to noise in input and in annotations.
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Ultrafast genome-wide scan for SNP-SNP interactions in common complex disease. (Prabhu & Peer, Genome Research)

Goal: Sampling approach to detecting epistasis:

SNP-SNP interactions, cant test
12 ~10

Method: Randomization technique (10-100x faster)

focusing on small groups of cases (with guarantees of coverage!) interacting SNPs (including calcium channel interactions) work together to create phenotypes.

Result: On bipolar GWAS data set, nd signicant Conclusion: There is hope for nding SNPs that
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CACNA2D4 + others

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Utility of gene-specic algorithms for predicting pathogenicity of uncertain gene variants. (Crockett et al, JAMIA)

Goal: Assess the value of generic vs. specic

predictors of impact of genetic variations.

Method: Naive Bayes classier built for 20 genes

and compared to generic tools (SIFT etc...) tools.

Result: Gene-specic often outperform generic Conclusion: Detailed biology matters, and it is
probably overly optimistic to expect variants to be triaged with general purpose tool.
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Complex-disease networks of trait-associated single-nucleotide polymorphisms (SNPs) unveiled by information theory. (Li et al, JAMIA)

Goal: GWAS hits may reveal complex disease

modularity and suggest drug repositioning. GWAS hits, GO annotations.

Method: Compute phenotype similarity based on Result: 177 disease traits connected, similarity
correlates with shortest protein interaction distance.

Conclusion: GWAS hits are not only individually

useful, but in aggregate for GWAS repurposing.

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A vector space model approach to identify genetically related diseases. (Sarkar, JAMIA)

Goal: Combine information from literature and

genome resources to link diseases based on similarity.

Method: Vector space model on OMIM, Genbank,

Medline. Apply to Alzheimers & Prader-Willi. suggest underlying common pathways.

Result: A constellation of associated diseases which Conclusion: There is a continuing hunger to reconceptualize our taxonomy of disease.
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A whole-cell computational model predicts phenotype from genotype (Karr et al, Cell)

Goal: Build the rst whole-cell model of a living cell. Method: 27 interacting subsystem simulations using
several simulation techniques.

Result: Remarkably able to recapitulate several

experimental measures, and predicts others.

Conclusion: Comprehensive whole-cell models of

bacterial are here, and eucaryotes are the next big challenge.

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Model recapitulates literature.

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Cancer

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An integrated approach to identify causal network modules of complex diseases with application to colorectal cancer. (Wen et al, JAMIA)

Goal: Find causal expression modules for complex

diseases (vs. consequential)

Method: Use linear programming to dene modules,

apply to transcriptional control of colorectal cancer.

Result: DNA methylation of TFs may be causal. Conclusion: Regulation of expression is an emerging
method for understanding disease etiology.
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Rows = modules, Cols = (N)ormal, Colon Cancer

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Systematic identication of genomic markers of drug sensitivity in cancer cells. (Garnett et al, Nature)

Goal: Find cancer genes that are biomarkers for

drug sensitivity.

Method: Screen cancer lines with 130 drugs, Result: Unexpected sensitivities, e.g. EWS
histology in determining best treatments.

associate drug sensitivity with genetic changes. translocation to poly(ADP-ribose) polymerase (PARP) inhibitors.

Conclusion: Genetic proles may supplement

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Circle = drug-gene (biomarker) association, size = # of lines screened

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Top associations
black: expression red: mutation blue: copy # green: tissue

Signicant genes for predicting sensitivity and resistance to dasatinib

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Whole-genome analysis informs breast cancer response to aromatase inhibition. (Ellis et al, Nature)

Goal: Correlate clinical response to aromatase Method: Sequence tumor/normal and assess
mutations, map to pathways.

inhibitors with genomic features of breast cancer.

Result: 18 genes identied, MAP3K1=low grade, Conclusion: Individualized cancer therapy will
become the norm.

TP53 = high grade. GATA3 = aromatase response. Distinct phenotypes associated with distinct somatic mutation patterns.

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Quantitative image analysis of cellular heterogeneity in breast tumors complements genomic proling. (Yuan et al, Science TM)

Goal: Integrate histology and genomics to improve

prognosis of breast cancer.

Method: Create predictor of survival in ER-neg

data sources.

breast cancer integrating imaging and expression.

Result: Combined predictor outperforms individual Conclusion: Traditional pathology needs to integrate
genomic measurements into diagnosis and prognosis measures.
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Conicting biomedical assumptions for mathematical modeling: the case of cancer metastasis. (Divoli et al, PLOS Comp Bio)

Goal: Understand differences in expert models of

key biomedical process: cancer metastasis

Method: 28 experts queried in structured way for

leaves bloodstream!

views of biology of metastasis (MD, PhD, MD/PhD). Markov modeling.

Result: Biggest disagreement: when cancer enters/ Conclusion: Expert opinion for modeling exercises is
divergent/incompatible. Modelers beware.
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1 expert = no comment 28 experts, 32 opinions!

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Drugs

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Systematic identication of pharmacogenomics information from clinical trials. (Li & Lu, J Biomed Inf)

Goal: Evaluate clinicaltrials.gov as source for druggene-disease relationships. CT.gov.

Method: NLP approach for identifying d-g-dz in Result: 74% accuracy by human review. Several
associations not in PharmGKB.

Conclusion: Clinicaltrials.gov can serve as a preview

of biomedical knowledge before publication.
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Use of genome-wide association studies for drug repositioning (Sanseau et al, Letter to Nature Biotech)

Goal: Use the GWAS investment to understand

drug opportunities.

Method: Find GWAS gene hits and compare

associated trait with drug indication.

Result: When trait matches indication, condence.

When trait doesnt match indication, repurpose.

Conclusion: GWAS results give a rich insight into

molecular underpinnings of disease, with multiple uses.
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Analysis of functional and pathway association of differential co-expressed genes: a case study in drug addiction. (Li et al, J Biomed Inf)

Goal: Seek genetic pathways common to addiction

disorders.

Method: Co-expression meta-analysis to expression

data for: alcohol, cocaine, heroin.

Result: Common pathways: electron transport,

towards a shared/spectrum view of disease.

synaptic transmission, cell migration, insulin, energy, dopamine, NGF signalling, locomotor behavior.

Conclusion: There is a trend in neuropsychiatry

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Shout outs...
Automatic ltering and substantiation of drug safety signals. (Bauer-Mehren et al, PLOS Comp Bio)

Result: Able to assign risk of QT prolongation based

on molecular networks for several psych drugs.

Literature based drug interaction prediction with clinical assessment using electronic medical records: novel myopathy associated drug interactions. (Duke et al, PLOS Comp Bio)

Result: Novel predictions for myopathy with strong

evidence.
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Delivery

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A clinician-driven automated system for integration of pharmacogenetic interpretations into an electronic medical record. (Hicks et al, Clin Pharm & Ther) Incorporating personalized gene sequence variants, molecular genetics knowledge, and health knowledge into an EHR prototype based on the Continuity of Care Record standard. (Jing et al, J. Biomed. Inf.) Operational implementation of prospective genotyping for personalized medicine: the design of the Vanderbilt PREDICT project. (Pulley et al, Clin. Pharm & Ther)
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Identifying personal genomes by surname inference. (Gymrek et al, Science)

Goal: Develop methods to reidentify study subjects. Method: Take advantage of coinheritance of Ychromosome & surname, combine with other public data sources. individuals who participate in public sequencing projects. similar in 2005. We need social mechanisms to disallow this.
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Result: Demonstrated ability to identify specic Conclusion: 15 year old in U.K. did something

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A novel, privacy-preserving cryptographic approach for sharing sequencing data. (Cassa et al, JAMIA)

Goal: Securely transmit genome sequence data. Method: Use subset of sequence as a shared secret
key to entire sequence.

Result: Robust to sequencing errors, population

structure, sibling disambiguation.

Conclusion: Can protect sensitive parts of genome

by using less sensitive subset as a key.
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Disclosing pathogenic genetic variants to research participants: quantifying an emerging ethical responsibility. (Cassa et al, Genome Research)

Goal: Quantify the amount of clinically signicant

genomic variants that may need to be disclosed. extrapolated estimates of clinically signicant variation. Will grow by 37% in next 4 years. 2000/person. overwhelm genomic medicine implementations.

Method: Apply recent recommendations to

Result: 4000-18000 variants qualify for disclosure. Conclusion: The incidentalome is here, and it could
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An Altered Treatment Plan Based on Direct to Consumer (DTC) Genetic Testing: Personalized Medicine from the Patient/Pin-cushion Perspective (Tenenbaum et al, J Pers Med)

Goal:

Can DTC information be used to predict and prevent disease? woman to predict high risk of clotting.

Method: 23andme DTC data used for pregnant Result: Anticoagulants offered to patient. No clots.
Emergency C-section for unrelated reasons. their providers to use it.

Conclusion: Cs who get DTC genetic data expect

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Pharmacogenomics in the pocket of every patient? A prototype based on quick response codes. (Samwald & Adlassnig, JAMIA)

Goal: Give consumers control of access to their

genotype for pharmacogenomics.

Method: Create Medicine safety barcode (QR). Result: Can encode genotypes, and provide local
access to interpretation on web. No large scale infrastructure required.

Conclusion: Consumers can use existing technology

to control access to their genetic measurements.
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2012 Crystal ball...

Cloud computing will contribute to major biomedical discovery. Informatics applications to stem cell science will increase Immune genomics will emerge as powerful data Flow cytometry informatics will grow Molecular & expression data will combine for drug repurposing Exome sequencing will persist longer than expected Progress in interpreting non-coding DNA variations
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2012 Crystal ball...

Cloud computing will contribute to major biomedical discovery. Informatics applications to stem cell science will increase Immune genomics will emerge as powerful data Flow cytometry informatics will grow Molecular & expression data will combine for drug repurposing Exome sequencing will persist longer than expected Progress in interpreting non-coding DNA variations
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2013 Crystal ball...

Increased focus on methods to untangle regulatory control of clinical phenotypes Rare variant GWAS with exomes & genomes Microbiome integrated with immunology & metabolomics, and disease risk. Emphasis on non European-descent populations for discovery of disease associations Mobile computing resources for genomics Crowd-based discovery in translational bioinformatics
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Thanks.
russ.altman@stanford.edu

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