Bioinformatics ApS. Founded in February 2002 with investment from Biovision Founders: Staff working...

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Bioinformatics ApS
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Page 1: Bioinformatics ApS. Founded in February 2002 with investment from Biovision Founders: Staff working at the Bioinformatics Research Center, Aarhus University.

Bioinformatics ApS

Page 2: Bioinformatics ApS. Founded in February 2002 with investment from Biovision Founders: Staff working at the Bioinformatics Research Center, Aarhus University.

Bioinformatics ApS

• Founded in February 2002 with investment from Biovision

• Founders: Staff working at the Bioinformatics Research Center, Aarhus University

• Employees: 2 software developers

Page 3: Bioinformatics ApS. Founded in February 2002 with investment from Biovision Founders: Staff working at the Bioinformatics Research Center, Aarhus University.

Founders

• Leif Schauser, Ph.D. (CEO): Associate Professor, Molecular Biology, Bioinformatics Research Institute

• Jotun Hein, Ph.D. (Member of BoD): Professor in Bioinformatics at Oxford University

• Mikkel Schierup, Ph.D. (CSO): Associate Professor, Biology, Bioinformatics Research Institute

• Christian Storm, Ph.D. (CTO): Associate Professor, Computer Science, Bioinformatics Research Institute

Page 4: Bioinformatics ApS. Founded in February 2002 with investment from Biovision Founders: Staff working at the Bioinformatics Research Center, Aarhus University.

Strategy

• Develop leading bioinformatics tools designed for association studies

• Branding the software

• Collaborations with pharmacogenomics industry

– Disease genes, adverse drug reactions

• Extend product suite to include other bioinformatics solutions (databases, comparative genomics)

Page 5: Bioinformatics ApS. Founded in February 2002 with investment from Biovision Founders: Staff working at the Bioinformatics Research Center, Aarhus University.

Drug target hunting

Microarray analysis Disease gene mapping

100s of targets,not necessarilyrelevant

Mb of genomic sequence,Power dependentRequires high resolution

Problems:Tissues, controls,Limited by array

Problems:Sampling, modeling,penetrance

Page 6: Bioinformatics ApS. Founded in February 2002 with investment from Biovision Founders: Staff working at the Bioinformatics Research Center, Aarhus University.

GeneRecon

• Association mapping using all markers at the same time and all other available information

• Fully probabilistic approach

Input:SNPs or microsattelites

Disease and control group

Output:Localisation of disease

Page 7: Bioinformatics ApS. Founded in February 2002 with investment from Biovision Founders: Staff working at the Bioinformatics Research Center, Aarhus University.

GeneRecon - implementation

• C++ program (>10.000 lines of code)

• Multiplatform (Unix, Windows, MacOSX)

• Amenable to parallelization

• Bayesian MCMC approach

Page 8: Bioinformatics ApS. Founded in February 2002 with investment from Biovision Founders: Staff working at the Bioinformatics Research Center, Aarhus University.

GeneRecon - implementation

• 10 million recalculations/hour

• Different models of disease transmission

• Diploid data with unknown phase

• Thorough tests for calculations

Page 9: Bioinformatics ApS. Founded in February 2002 with investment from Biovision Founders: Staff working at the Bioinformatics Research Center, Aarhus University.

GeneRecon – output

• Disease gene location (full distribution)

• Disease-causing haplotypes

• Estimation of phenocopies

• Penetrance

• Date the origin of disease

Page 10: Bioinformatics ApS. Founded in February 2002 with investment from Biovision Founders: Staff working at the Bioinformatics Research Center, Aarhus University.

GeneRecon - collaborations

• Scandinavian medium sized biotechnological companies– Proprietary dataset under analysis

• Danish University Hospital– Schizophrenia data are currently being collected

Page 11: Bioinformatics ApS. Founded in February 2002 with investment from Biovision Founders: Staff working at the Bioinformatics Research Center, Aarhus University.

Disease mappingPedigree Analysis: Association Mapping:

Pedigree known

Few Meiosis (max 100s)

Many Generations

Resolution: cMorgans (Mbases)Pedigree sampled

Many Meiosis (>104)

Resolution: 10-4 Morgans (Kbases)

Tim

e

rM

D

rM

D

Page 12: Bioinformatics ApS. Founded in February 2002 with investment from Biovision Founders: Staff working at the Bioinformatics Research Center, Aarhus University.

Linkage Disequilibrium (LD)

Page 13: Bioinformatics ApS. Founded in February 2002 with investment from Biovision Founders: Staff working at the Bioinformatics Research Center, Aarhus University.
Page 14: Bioinformatics ApS. Founded in February 2002 with investment from Biovision Founders: Staff working at the Bioinformatics Research Center, Aarhus University.

Haplotypes

Haplotypes:

SNPs:

A

T

G

C

C

A

{A,T} {C,G} {A,C}

2m-1

Page 15: Bioinformatics ApS. Founded in February 2002 with investment from Biovision Founders: Staff working at the Bioinformatics Research Center, Aarhus University.

The Human Genome http://www.sanger.ac.uk/HGP/

1

2 3

4 56 7 8 9

X

Y15141312

10 11212019

181716

22

3 billion base pairs per haploid genome

30.000-40.000 genes

Page 16: Bioinformatics ApS. Founded in February 2002 with investment from Biovision Founders: Staff working at the Bioinformatics Research Center, Aarhus University.

SNP facts

http://www.ncbi.nlm.nih.gov/SNP/

• For 2 complete haplotype genomes, there are about 3 million SNP differences (>1 SNP / kb).

• Currently 3 mio. SNPs in database

RefSNP with frequency with genotype

3.079.086 196.054 32.101

Page 17: Bioinformatics ApS. Founded in February 2002 with investment from Biovision Founders: Staff working at the Bioinformatics Research Center, Aarhus University.

Large scale survey of LDReich et al. (2001)

Page 18: Bioinformatics ApS. Founded in February 2002 with investment from Biovision Founders: Staff working at the Bioinformatics Research Center, Aarhus University.

Recent LD studies

• LD extends over considerable distance in most populations• African populations show less LD than European

populations• Small, isolated populations (e.g. Saami, Evenki) show

increased LD• Founder populations (e.g. Finland, Sardinia) do not always

show increased LS

• Evidence for heterogeneity in LD along chromosomes– Haplotype blocks– Recombination hotspots

Page 19: Bioinformatics ApS. Founded in February 2002 with investment from Biovision Founders: Staff working at the Bioinformatics Research Center, Aarhus University.

Genetic Basis for DiseaseMonogenic

Cystic Fibrosis

Huntington’s Disease

Sickle Cell Anemia

Polygenic

Azheimer’s disease

Schizophrenia

Hereditaray Heart Disease

Astma

Page 20: Bioinformatics ApS. Founded in February 2002 with investment from Biovision Founders: Staff working at the Bioinformatics Research Center, Aarhus University.
Page 21: Bioinformatics ApS. Founded in February 2002 with investment from Biovision Founders: Staff working at the Bioinformatics Research Center, Aarhus University.

Cystic fibrosis: a case study

Traditional analysis Bayesian MCMC sampling

Page 22: Bioinformatics ApS. Founded in February 2002 with investment from Biovision Founders: Staff working at the Bioinformatics Research Center, Aarhus University.

The market

• All major pharmaceutical and many biotech companies conduct genetic studies– Disease association (drug target identification)– Adverse drug response (pharmacogenomics)– Tailored drug administration

• Outsourcing of non-core activities

Page 23: Bioinformatics ApS. Founded in February 2002 with investment from Biovision Founders: Staff working at the Bioinformatics Research Center, Aarhus University.

Timeline for drug discovery # Targets Discovery (5 yrs)

5000 Population study I

Pre-Clinical (1 yr)

50

Clinical (6 yrs)5 Population study II

Review (2 yrs)

1

Marketed

Page 24: Bioinformatics ApS. Founded in February 2002 with investment from Biovision Founders: Staff working at the Bioinformatics Research Center, Aarhus University.

Cambridge Healthtech Institute: SNP-research market could reach

$1.2 billion by 2005• Annual expenditures on SNP research:

– $158 million in 2001 – $1.2 billion in 2005 (estimated): 7 fold growth

• Increasing interest in pharmacogenomics-or tailoring treatment to patients based on their genomic profiles-by pharmaceutical, biotechnology, and genomic tools companies.

Page 25: Bioinformatics ApS. Founded in February 2002 with investment from Biovision Founders: Staff working at the Bioinformatics Research Center, Aarhus University.

Factors influencing SNP research

0

20

40

60

80

100

2000 2001 2002 2003

Price / SNP(Cents)

Identified SNPs(x100.000)

Investigations(x10)

Average size ofinvestigation(x20)

Page 26: Bioinformatics ApS. Founded in February 2002 with investment from Biovision Founders: Staff working at the Bioinformatics Research Center, Aarhus University.

Example

• DeCode typed 10.000 markers in all Icelanders (250.000)

Page 27: Bioinformatics ApS. Founded in February 2002 with investment from Biovision Founders: Staff working at the Bioinformatics Research Center, Aarhus University.

Needs of the market

• Detailed understanding of population biology

• Extract signals from noisy data (power)• Efficient algorithms that provide quick and precise answers

Page 28: Bioinformatics ApS. Founded in February 2002 with investment from Biovision Founders: Staff working at the Bioinformatics Research Center, Aarhus University.

Comparative Genomics

• Gene finding (Correct annotation is crucial)• Identifying important residues in drug

targets (HIV, proteins etc.)• Identifying regulatory sequences, networks

Page 29: Bioinformatics ApS. Founded in February 2002 with investment from Biovision Founders: Staff working at the Bioinformatics Research Center, Aarhus University.

Future

Disease gene finding:

GeneRecon

Databasesolutions Comparative Genomics

Page 30: Bioinformatics ApS. Founded in February 2002 with investment from Biovision Founders: Staff working at the Bioinformatics Research Center, Aarhus University.

Haplotypes

Experimental methods of determining Haplotypes:

•Egg & Sperm Sequencing

•Cell Lines with Lost Chromosomes

•Sequencing Clones Spanning SNPs

These methods are very expensive so computational reconstruction of haplotypes from SNPs is preferable.

Haplotypes:

SNPs:

A

T

G

C

C

A

{A,T} {C,G} {A,C}

2m-1

Page 31: Bioinformatics ApS. Founded in February 2002 with investment from Biovision Founders: Staff working at the Bioinformatics Research Center, Aarhus University.

ParametersBayesian Analysis, i.e. all parameters have assigned distributions.

Markov Chain Monte Carlo allows the calculation of posterior (post-data) calculation of parameters and quantities of interest.

Page 32: Bioinformatics ApS. Founded in February 2002 with investment from Biovision Founders: Staff working at the Bioinformatics Research Center, Aarhus University.

The Shattered Coalescent(Morris, Whittaker & Balding,2002)

Advantages: Allows for multiple origins of the disease mutant + sporadic occurances of the disease without the mutation (phenocopies)