Medicine in the 21st century: IT as a «magic bullet»?

The virtual patient: a challenge for information technology and data integration

Prof. Manuel C. Peitsch

VP Biological Systems Research, PMI R&D

Chairman of the Board of Directors, Swiss Institute of Bioinformatics

Information, Computational and Mathematical Sciences

2Medicine in the 21st century: IT as a «magic bullet»?

Inventory of challenge categories

• Data, Information and Knowledge management

• Knowledge representation(s)

• Model building

• Using Models

• Simulation

• Verification / validation

3Medicine in the 21st century: IT as a «magic bullet»?

The Challenge of Data, Information & Knowledge Management

• Data, Information and Knowledge are:– The products of Science … which become the

input to build new science and applications that benefit society.

• However:– They need to be managed!

• Why?

4Medicine in the 21st century: IT as a «magic bullet»?

A Web of Data, Information and Knowledge, …

0.5 1.50.5 1.50.5 1.5

S1

S2

L3

L4

E5

K6

G7

L8

D9

G10

A11

K12

K13

A14

V15

G16

G17

L18

G19

K20

L21

G22

K23

D24

A25

V26

E27

D28

L29

E30

S31

V32

G33

K34

G35

A36

V37

H38

D39

V40

K41

D42

40 30 20 10

V43

L44

D45

S46

V47

L48

1

S1

S2

L3

L4

E5

K6

G7

L8

D9

G10

A11

K12

K13

A14

V15

G16

G17

L18

G19

K20

L21

G22

K23

D24

A25

V26

E27

D28

L29

E30

S31

V32

G33

K34

G35

A36

V37

H38

D39

V40

K41

D42

40 30 20 10

V43

L44

D45

S46

V47

L48

1

Mass (m/z)

% In

tens

ity

1500 2200 2900 3600 4300 5000

50

100

3876

.3

2738

.9

2324

.7

2495

.6

3832

.1

4174

.9

2081

.1

4503

.2

2981

.5

2623

.8

3321

.5

3717

.1

3491

.6

4059

.6

2795

.8

2209

.3

3094

.331

67.7

4290

.3

1838

.1

1652

.2

1911

.5

b27

b42 - D

b30

b38

y39 -D9

y11

y27

y33

y18 [M+H]+

y35

b39-D

b28-D (y26)

y24 -Db24-D (y22)

y20 -D

b23

b45 - D

5Medicine in the 21st century: IT as a «magic bullet»?

… with a history of exponential growth

6Medicine in the 21st century: IT as a «magic bullet»?

The Ancient Dream of a Global Library One stop shop for all knowledge Peitsch MC (2007) Expert Opinion in Drug Discovery 2:299-304.

Despite the IT revolution, this is still not a reality … and we are very for from it!

7Medicine in the 21st century: IT as a «magic bullet»?

The Challenge of Knowledge Representation

BioPAX: is an ontology (formal knowledge representation system)

Demir et al., Nature Biotechnology 2010, 28:935-942

8Medicine in the 21st century: IT as a «magic bullet»?

The Challenge of Knowledge Representation

The Biological Expression Language (BEL) allows the management and “operationalization” of biological facts (http://belframework.org/)

Shouldn’t these concepts be merged into a new concept?

9Medicine in the 21st century: IT as a «magic bullet»?

The Challenge of Model Building

Experimental Data

Mechanism

A Collection of Cause and Effect Scientific

Knowledge

Data-driven representation of mechanistic networks supported by prior knowledge

10Medicine in the 21st century: IT as a «magic bullet»?

Understanding DiseaseMechanisms

Understanding DiseaseMechanisms

Systems Response ProfilesSystems Response Profiles

Network ModelsNetwork Models

11Medicine in the 21st century: IT as a «magic bullet»?

The Challenge of Model BuildingDealing with the fundamental contradictions and ambiguities associated with

assimilating scientific findings from disparate biological experiments and quality issues associated with manual and algorithm-driven collation methods

12Medicine in the 21st century: IT as a «magic bullet»?

Inflammation Response Network:23 sub-networks in 9 cell and tissue categories

1320 nodes and 1619 edges

13Medicine in the 21st century: IT as a «magic bullet»?

The Challenge of Using Models

Hoeng JC et al. (2011) Drug Discovery Today. doi:10.1016/j.drudis.2011.11.008

14Medicine in the 21st century: IT as a «magic bullet»?

The Challenge of Using Models

• Patient stratification based on drug response.

• Evaluating AE/Tox risk linked to exposure

• Diagnostics

…BUT…

What about personalization based on Omics / Genetics?

15Medicine in the 21st century: IT as a «magic bullet»?

The Challenge of Simulation

Kholodenko BN, Demin OV, Moehren G, Hoek JB. Quantification of short term signaling by the epidermal growth factor receptor. J Biol Chem. 1999 Oct 15;274(42):30169-81

1. Process Diagram2. Mathematical

Expressions3. Setting parameters4. Running simulations

1

23

4

16Medicine in the 21st century: IT as a «magic bullet»?

Entelos PhysioLab allows the assessment of diversity and mechanistic variability on individual patient and population predictions

16

17Medicine in the 21st century: IT as a «magic bullet»?

Cardiovascular PhysioLab clinical phenotype is constrained by many individual measurements and population statistics

17

18Medicine in the 21st century: IT as a «magic bullet»?

Uncertainty in 

UnderlyingMechanistic

Diversity……9p21SMC 

proliferationLCATactivity

LDLRlevels

CETP/LPLactivity

hepatic TG

ABCA1activity

ObservedSub‐population 

Variability

Virtual patients and population capture phenotypic range by modeling underlying mechanistic diversity

Population level distributions (e.g. Framingham, NHANES)

T2D +/‐

CAD Hyperlipidemia statin

non‐responders

19Medicine in the 21st century: IT as a «magic bullet»?

Confidence intervals around predictions can achieved by assigning alternate prevalence probabilities to virtual populations

19

20Medicine in the 21st century: IT as a «magic bullet»?

Impact of alternate prevalence weighted virtual populations on clinical trial design

• Right clinical trial design– Optimal dose, regimen, duration

– Competitive differentiation

• Right patients– Responder/non-responder subpopulations

– Biomarker patterns (efficacy and safety)

• Systemic risk management– Alternate population-level hypotheses for best-case and worst-case

scenarios

– Testable hypotheses via early-phase biomarker patterns

20

21Medicine in the 21st century: IT as a «magic bullet»?

The Challenge of Verification

Independent verification of complex research processes / methods is increasingly necessary

… and so is the verification of the output …

22Medicine in the 21st century: IT as a «magic bullet»?

How Bright Promise in Cancer Testing Fell Apart

23Medicine in the 21st century: IT as a «magic bullet»?

Academic efforts: DREAM

24Medicine in the 21st century: IT as a «magic bullet»?

Commercial efforts: IMPROVER

P. Meyer et al., Nature Biotechnology 2011, 29:811-815J. Hoeng et al., Bioinformatics 2012, in press

25Medicine in the 21st century: IT as a «magic bullet»?

Q&A

Thank you for your attention…