Making Medicine more personal, precise, and predictive Is ... › uploads ›...
Transcript of Making Medicine more personal, precise, and predictive Is ... › uploads ›...
![Page 1: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/1.jpg)
Making Medicine more personal, precise, and predictive
Is so-called clinical BigData actually sufficient?
Alexander Hoffmann
http://www.signalingsystems.ucla.edu
http://www.qcb.ucla.edu
![Page 2: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/2.jpg)
Medicine is about people
… and molecules !
![Page 4: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/4.jpg)
DNA & genes
chromosome epigenetics
molecular networks
cellular function
cell-cell interactions
organ function
Human Health is multi-scale complexity
Billion-fold length scales
![Page 5: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/5.jpg)
Human Health is multi-scale complexity
Billion-fold time scales
100
![Page 6: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/6.jpg)
The Groundhog
Feb 2 • cloudy
• sunny
March • early Spring
• prolonged winter
Biomolecular measurement
Disease outcome Whether drug works
Statistical Model
![Page 7: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/7.jpg)
Predicting Human Health
RNA
statistical model
Bio
marke
rs
Diagn
osis/Th
erap
y
![Page 8: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/8.jpg)
Some biomarkers are very accurate
Sickle cell anemia: 100% accurate
![Page 9: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/9.jpg)
Some biomarkers are quite accurate
BRCA1/2 mutation
![Page 10: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/10.jpg)
And we understand how they work
![Page 11: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/11.jpg)
But predictive power of many biomarkers is limited - diseases are complex -
Salles et al 2011
![Page 12: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/12.jpg)
Combining multiple measurements can improve predictive power
Lou Staudt NCI
![Page 13: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/13.jpg)
Combining multiple measurements can improve predictive power
Lou Staudt NCI
![Page 14: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/14.jpg)
Combining multiple measurements can improve predictive power
genome
clinical records
statistical model
molecular data / biomarkers
improve diagnosis
personalize therapy
reduce costs
clinical p
rese
ntatio
n
![Page 15: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/15.jpg)
Big Data in Biosciences
![Page 16: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/16.jpg)
The Precision Medicine Opportunity: Predictive power based on correlations derived from previous patients
genome
epigenomes transcriptomes
proteomes metabolomes
improve diagnosis
identify patient cohorts for studies
personalize therapy
reduce costs
improve treatment/ drug pipeline
clinical p
rese
ntatio
n
microbiomes
clinical records / UC BRAID
statistical model
![Page 17: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/17.jpg)
The Holy Grail:
Precision Health Care
genomes
epigenomes transcriptomes
proteomes
clinical records
metabolomes
statistical
model
prevent disease
life style adjustment
statistical
model
food intake exercise
sleep patterns environmental
microbiomes happiness/stress
mHealth monitors heart, pressure, temperature, sugar, perspiration, urine
prophylactic treatment
precision treatment
earliest intervention
![Page 18: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/18.jpg)
The Holy Grail: Precision Health Care What will it take?
The predictive power of statistical models is a function of
the amount and quality of training data.
![Page 19: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/19.jpg)
The Holy Grail: Precision Health Care What will it take?
How much training data ?
Genome Environment
Consider the variation
Life Style
10 Million SNPs (variable locations)
210,000,000 = 103,000,000
Millions of variants
Millions of variants
106 106
>>>> people ever on the planet
x x = “gazzilian”
Epigenome
![Page 20: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/20.jpg)
Is there an alternative approach?
![Page 21: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/21.jpg)
Airplanes: amazing complex but predictable
Boeing 737: 367,000 parts
Humans: 20,000 genes, 200,000 proteins, 37 × 10^12 cells
1 fatality in 2 x 10^9 miles flown: safest mode of transport
![Page 22: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/22.jpg)
Airplanes are so predictable that flight can be simulated !
![Page 23: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/23.jpg)
The reason for airplanes predictability:
Based on physical principles, and these are described in mathematical equations
“Bernoulli equations”
![Page 24: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/24.jpg)
Two Algorithmic Worlds
Statistical Mechanistic
a + b = c
Agnostic of - Knowledge - Mechanism of causation - Scale
P(a,b) –> c
Precise, but requires knowledge
![Page 26: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/26.jpg)
Predicting Human Health
RNA mechanistic
model
mechanistic
model
mechanistic
model
mechanistic
model
![Page 27: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/27.jpg)
Identify components: parts list Learn physical principles that connect them Learn how each part works in context of the system Build computational model and simulate Physiological functions
Developing Mechanistic Models
![Page 28: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/28.jpg)
2015: NIH budget: $30 billion 300,000 researchers 2,500 institutions
0
5.000.000
10.000.000
15.000.000
20.000.000
25.000.000
30.000.000
35.000.000
1950 1960 1970 1980 1990 2000 2010
The NIH has invested > $500,000,000,000 into biomedical knowledge
![Page 29: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/29.jpg)
DNA & genes
chromosome epigenetics
molecular networks
cellular function
cell-cell interactions
organ function
Biology / Life Sciences: at every scale
Molecular Biology
Biochemistry Cell
Biology Physiology
![Page 30: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/30.jpg)
Biomedical knowledge
![Page 31: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/31.jpg)
a
b e
IB IB
AAAAA
IKK
IB IB
IB
IKK
IKK
IB
Inflammatory Signals
NFB target genes
= k13 * NFBnucleus
+ k-4 * IBaNFBn
+ k-5 * IBbNFBn
+ k-6 * IBeNFBn
+ k7 * IBaNFBn
+ k8 * IBbNFBn
+ k9 * IBeNFBn
- k-13 * NFBcytoplasm
- k4 *
IBa NFBn
- k5 *
IBb NFBn
- k6 *
IBe NFBn
d NFBn
dt = gain - loss
Nuclear Import
Dissociation
Dissociation
Dissociation
Bound IB Deg.
Bound IB Deg.
Bound IB Deg.
Nuclear Export
Association
Association
Association
The challenge of extracting knowledge
![Page 32: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/32.jpg)
x x
x
x
x
x
x x
x x
x
x x x
x
x
x
x
t
h
Are knowledge-based models necessary?
R2=acceptable t √h
1. Knowledge-based models allow for predictions beyond the training range.
Newton h
t
![Page 33: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/33.jpg)
x
2. Knowledge-based models interpret confusingly complex data
Where is the outlier?
Y
x x x x x x x
t
Y
Y X
Knowledge: the system oscillates
Are knowledge-based models necessary?
The person who will become very sick.
??
![Page 34: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/34.jpg)
t
Y
3. Knowledge-based models allow for predictions when relationships are non-linear. - Essential for Drug Dosing
Y X
Are knowledge-based models necessary?
![Page 35: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/35.jpg)
Precision Health Care
Genomes
Behavioral factors
Environmental factors
Molecular diagnostics Epigenomes
Algorithmic Synthesis
KNOWLEDGE
big data
mHealth Monitors
![Page 36: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/36.jpg)
Life Sciences
Medical School Engineering
Health Systems
![Page 37: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/37.jpg)
![Page 38: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/38.jpg)
38
Awesome measurement
capabilities
Electronic clinical data
Computational Modeling
Predictive Biosciences that accounts for the dynamic,
heterogenous genotype-phenotype relationship at all
scales, e.g. cells, organs, organisms, ecosystems.
“Precision medicine” that combines
“personalized medicine” and “predictive pharmacology”,
culminating in “virtual clinical trials”.
The promises of
Big Data Big Knowledge based on
Molecular Biology Biochemistry
Genetics
![Page 39: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/39.jpg)
Research Training - Data generators need QC skills: workshops - Masters and Professional Masters Programs
Education - Graduate Program in QC Biosciences = Bioinformatics, Biomedical
Informatics, Computational & Systems Biology - All Biosciences Graduate programs require more quantitative courses - Flagship Undergraduate Programs in Bioinformatics and Computational
& Systems Biology will help catalyze changes in Life Sciences BSc’s 39
Research - Excellence in Bioinformatics & Genomics - Excellence in Dynamical and Stochastic Processes - Knowledge-based modeling for big-data analysis across scales - Catalyze and enable large grant applications - Collaborate to provide computational expertise - Spin out technology, methodology, tools, biomarkers
![Page 40: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/40.jpg)
Predicting Immune Responses
RNA
mechanistic
model
mechanistic
model
![Page 41: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/41.jpg)
Predicting cell populations based on molecular network
![Page 42: Making Medicine more personal, precise, and predictive Is ... › uploads › 15e64bcec713fe914d… · Making Medicine more personal, precise, and predictive Is so-called clinical](https://reader035.fdocuments.net/reader035/viewer/2022070712/5eced4e6194eb40ca3646190/html5/thumbnails/42.jpg)
Marcelo Behar
Max Shokhirev
signalingsystems.ucla.edu
http://www.qcb.ucla.edu