Title slide Genetics/Genomics in Hepatitis and Liver … · Genetics/Genomics in Hepatitis and...
Transcript of Title slide Genetics/Genomics in Hepatitis and Liver … · Genetics/Genomics in Hepatitis and...
![Page 1: Title slide Genetics/Genomics in Hepatitis and Liver … · Genetics/Genomics in Hepatitis and Liver Disease ... The Next Step after the Human Genome Project ... Simple Mendelian](https://reader031.fdocuments.us/reader031/viewer/2022022608/5b891de37f8b9abf5c8cffb2/html5/thumbnails/1.jpg)
Genetics/Genomics in Hepatitis and Liver Disease
Title slide
Scott L. Friedman MD
![Page 2: Title slide Genetics/Genomics in Hepatitis and Liver … · Genetics/Genomics in Hepatitis and Liver Disease ... The Next Step after the Human Genome Project ... Simple Mendelian](https://reader031.fdocuments.us/reader031/viewer/2022022608/5b891de37f8b9abf5c8cffb2/html5/thumbnails/2.jpg)
Overview
• Definitions / basics of genetics, genomics &
epigenetics
• Why learn about genetics and genomics?
• Applications of genomics in liver disease
- HCV response to Alpha IF – IL28B SNP
- SNPs that predict fibrosis progression in HCV
- Pharmacogenomics and hepatic drug toxicity
• Summary / Predictions
![Page 3: Title slide Genetics/Genomics in Hepatitis and Liver … · Genetics/Genomics in Hepatitis and Liver Disease ... The Next Step after the Human Genome Project ... Simple Mendelian](https://reader031.fdocuments.us/reader031/viewer/2022022608/5b891de37f8b9abf5c8cffb2/html5/thumbnails/3.jpg)
Genetics and Genomics - Definitions
Genetics – focus on single genes and their effects
Genomics – refers to the action of all genes in an organism
- concerned with the structure, function, evolution and mapping of
genomes
![Page 4: Title slide Genetics/Genomics in Hepatitis and Liver … · Genetics/Genomics in Hepatitis and Liver Disease ... The Next Step after the Human Genome Project ... Simple Mendelian](https://reader031.fdocuments.us/reader031/viewer/2022022608/5b891de37f8b9abf5c8cffb2/html5/thumbnails/4.jpg)
DNA to RNA
RNA
to protein
5'
Unwound
DNA
tRNA
mRNA
5' 3' 3'
5'
Transcription
Translation
NH2
C O O H
Peptide
A A A A
The Basics – DNA to RNA to Protein
![Page 5: Title slide Genetics/Genomics in Hepatitis and Liver … · Genetics/Genomics in Hepatitis and Liver Disease ... The Next Step after the Human Genome Project ... Simple Mendelian](https://reader031.fdocuments.us/reader031/viewer/2022022608/5b891de37f8b9abf5c8cffb2/html5/thumbnails/5.jpg)
Typical Gene Organization
CCAAT box
TATA box
Silencer
Enhancer
-35 -10
3' 5'
Core promoter
Ex1 Ex2 Ex3
Transcriptional unit
Regulatory unit
mRNA: AAAA
Transcription
NH2 - Met - aa-aa-aa-aa . . . aa - COOH Protein:
6
RNA: AAAA
CAP
![Page 6: Title slide Genetics/Genomics in Hepatitis and Liver … · Genetics/Genomics in Hepatitis and Liver Disease ... The Next Step after the Human Genome Project ... Simple Mendelian](https://reader031.fdocuments.us/reader031/viewer/2022022608/5b891de37f8b9abf5c8cffb2/html5/thumbnails/6.jpg)
Alternative Gene Splicing 5’
Gene transcription
Exon 2
3’
Exon 1 Exon 3 Exon 4
Splice B Splice A
Exon 2 Exon 1 Exon 3 Exon 4 Exon 1 Exon 3 Exon 4
AAAA
5’
3’ RNA
Protein A Protein B
mRNA mRNA
![Page 7: Title slide Genetics/Genomics in Hepatitis and Liver … · Genetics/Genomics in Hepatitis and Liver Disease ... The Next Step after the Human Genome Project ... Simple Mendelian](https://reader031.fdocuments.us/reader031/viewer/2022022608/5b891de37f8b9abf5c8cffb2/html5/thumbnails/7.jpg)
Genetic Code
Universal
Redundant
Wobble - 3rd base
Start = AUG = Met
Stop = UAA, UAG, UGA
Genetic Code
![Page 8: Title slide Genetics/Genomics in Hepatitis and Liver … · Genetics/Genomics in Hepatitis and Liver Disease ... The Next Step after the Human Genome Project ... Simple Mendelian](https://reader031.fdocuments.us/reader031/viewer/2022022608/5b891de37f8b9abf5c8cffb2/html5/thumbnails/8.jpg)
Assessment of Disease Risk using
Single Nucleotide Polymorphisms (SNPs)
• Single Base Variants found in > 1% of population
• ~ 300,000 Common SNPS per Genome
• Useful for Gene Discovery for Complex Diseases
Pt. A: ...CTGATACAATGCATC
Pt. B: ...CGGATACCATGTATC
Pt. C: ...CTGATGCCATGCATC
![Page 9: Title slide Genetics/Genomics in Hepatitis and Liver … · Genetics/Genomics in Hepatitis and Liver Disease ... The Next Step after the Human Genome Project ... Simple Mendelian](https://reader031.fdocuments.us/reader031/viewer/2022022608/5b891de37f8b9abf5c8cffb2/html5/thumbnails/9.jpg)
Insights from the
Human Genome Project
Project began in 1990, completed in 13 years
Transfer information to public for discovery
Consider ethical, legal, & social implications (ESLI)
FINDINGS:
• Only 2% of genome is genes
• 98% is “junk” DNA
• Sequence is >98.5% identical in all humans
- Including across races/ethnic groups
![Page 10: Title slide Genetics/Genomics in Hepatitis and Liver … · Genetics/Genomics in Hepatitis and Liver Disease ... The Next Step after the Human Genome Project ... Simple Mendelian](https://reader031.fdocuments.us/reader031/viewer/2022022608/5b891de37f8b9abf5c8cffb2/html5/thumbnails/10.jpg)
Humans Have Many Fewer Genes than Expected – Why?
Organism No. Genes
Drosophila (fruit fly) 13,600
Arabidopsis (flowering plant) 25,500
Mouse 23,000
Humans? 22,000!
Humans have large regions that don’t code for genes:
- highly conserved regions (e.g., long non-coding (linc) RNA)
- alternative splicing, which generates multiple transcripts from
single genes
- epigenetic regulation may be far more important in humans
![Page 11: Title slide Genetics/Genomics in Hepatitis and Liver … · Genetics/Genomics in Hepatitis and Liver Disease ... The Next Step after the Human Genome Project ... Simple Mendelian](https://reader031.fdocuments.us/reader031/viewer/2022022608/5b891de37f8b9abf5c8cffb2/html5/thumbnails/11.jpg)
Definition:
Changes in gene
expression or
cellular phenotype
without affecting the
DNA sequence
Epigenetics
![Page 12: Title slide Genetics/Genomics in Hepatitis and Liver … · Genetics/Genomics in Hepatitis and Liver Disease ... The Next Step after the Human Genome Project ... Simple Mendelian](https://reader031.fdocuments.us/reader031/viewer/2022022608/5b891de37f8b9abf5c8cffb2/html5/thumbnails/12.jpg)
ENCODE –
The Next Step after the Human Genome Project
ENCODE – “Encyclopedia of human DNA elements”
Goal: to identify all regions of transcription, transcription factor
association, chromatin structure and histone modification in
the human genome sequence
• A large consortium of scientists to explore all components
that influence gene expression and phenotype
• Results published in > 30 papers in 2012
![Page 13: Title slide Genetics/Genomics in Hepatitis and Liver … · Genetics/Genomics in Hepatitis and Liver Disease ... The Next Step after the Human Genome Project ... Simple Mendelian](https://reader031.fdocuments.us/reader031/viewer/2022022608/5b891de37f8b9abf5c8cffb2/html5/thumbnails/13.jpg)
ENCODE Highlights
• 80% of genome contains elements linked to biochemical fxns
DNA variants linked to disease lie within or near non-coding fxnl DNA elements
75% of the genome is transcribed at some point in cells
Genes that are highly interlaced with overlapping transcripts are synthesized
from both DNA strands – this has implications for the definition of a ‘gene’
• Doubled the number of known recognition sites for DNA
binding proteins
• Chromosome loops & twists enable communication between
distal elements
Ecker et al, Nature 489, 52-55, 2012
![Page 14: Title slide Genetics/Genomics in Hepatitis and Liver … · Genetics/Genomics in Hepatitis and Liver Disease ... The Next Step after the Human Genome Project ... Simple Mendelian](https://reader031.fdocuments.us/reader031/viewer/2022022608/5b891de37f8b9abf5c8cffb2/html5/thumbnails/14.jpg)
Why Learn about Genetics and
Genomics?
• Understanding of disease pathogenesis
• Define risk of disease
• Disease classification/definition
– Prognostic implications
– Optimize treatment strategies - timing of OLTx, mechanism-specific therapy
• Prevention strategies (eg DILD, ALD)
• Design and personalize new treatments
• Determine risk to children & family members
![Page 15: Title slide Genetics/Genomics in Hepatitis and Liver … · Genetics/Genomics in Hepatitis and Liver Disease ... The Next Step after the Human Genome Project ... Simple Mendelian](https://reader031.fdocuments.us/reader031/viewer/2022022608/5b891de37f8b9abf5c8cffb2/html5/thumbnails/15.jpg)
Haemochromatosis Wilson’s Disease
Cystic Fibrosis PFIC & BRIC
Alagille’s Syndrome
a1-Antitrypsin Deficiency
Glycogen Storage Diseases
Hepatic Porphyrias
Simple Mendelian Disorders
![Page 16: Title slide Genetics/Genomics in Hepatitis and Liver … · Genetics/Genomics in Hepatitis and Liver Disease ... The Next Step after the Human Genome Project ... Simple Mendelian](https://reader031.fdocuments.us/reader031/viewer/2022022608/5b891de37f8b9abf5c8cffb2/html5/thumbnails/16.jpg)
Hepatitis B & C Infection
Non-alcoholic fatty liver
Alcoholic Liver Disease
Primary Biliary Cirrhosis
Primary Sclerosing Cholangitis
Autoimmune Hepatitis
Complex Traits
![Page 17: Title slide Genetics/Genomics in Hepatitis and Liver … · Genetics/Genomics in Hepatitis and Liver Disease ... The Next Step after the Human Genome Project ... Simple Mendelian](https://reader031.fdocuments.us/reader031/viewer/2022022608/5b891de37f8b9abf5c8cffb2/html5/thumbnails/17.jpg)
MacGregor et al. Trends in Genetics 16, 131(2000).
Disease Heritability (%)
Asthma 60
Blood pressure 40-70
Bone mineral density 60-80
Cervical and lumbar disc degeneration 60-80
Insulin-dependent diabetes (IDDM) 70
Obesity 50-90
Osteoarthritis 50-90
Rheumatoid arthritis 60
Ulcerative colitis 50
Common Complex Disease Have a
Significant Genetic Component
![Page 18: Title slide Genetics/Genomics in Hepatitis and Liver … · Genetics/Genomics in Hepatitis and Liver Disease ... The Next Step after the Human Genome Project ... Simple Mendelian](https://reader031.fdocuments.us/reader031/viewer/2022022608/5b891de37f8b9abf5c8cffb2/html5/thumbnails/18.jpg)
Genotype with SNPs in predicted but
uncharacterized genes
Whole Genome Scans
Genotype with SNPs in known genes to
accelerate disease association studies
Candidate Gene Approach
Finding Disease Genes and Variants
![Page 19: Title slide Genetics/Genomics in Hepatitis and Liver … · Genetics/Genomics in Hepatitis and Liver Disease ... The Next Step after the Human Genome Project ... Simple Mendelian](https://reader031.fdocuments.us/reader031/viewer/2022022608/5b891de37f8b9abf5c8cffb2/html5/thumbnails/19.jpg)
Finding the gene “hypothesis-free”
Whole genome SNP scanning
• Use SNP map to “scan” whole genome in cases and
controls
• >2.7 million SNPs in current database
• Requires high throughput genotyping technology
• Used to be restricted to pharma companies, but no
longer - especially at Mount Sinai!
![Page 20: Title slide Genetics/Genomics in Hepatitis and Liver … · Genetics/Genomics in Hepatitis and Liver Disease ... The Next Step after the Human Genome Project ... Simple Mendelian](https://reader031.fdocuments.us/reader031/viewer/2022022608/5b891de37f8b9abf5c8cffb2/html5/thumbnails/20.jpg)
Impact of Genomics on Hepatitis and
Liver Disease
• Response to alpha IF in HCV
• Genetic Risk of fibrosis progression
in HCV
• Pharmacogenomics and drug
toxicity
![Page 21: Title slide Genetics/Genomics in Hepatitis and Liver … · Genetics/Genomics in Hepatitis and Liver Disease ... The Next Step after the Human Genome Project ... Simple Mendelian](https://reader031.fdocuments.us/reader031/viewer/2022022608/5b891de37f8b9abf5c8cffb2/html5/thumbnails/21.jpg)
60 M
b
Chromosome 19
A Polymorphism on Chromosome 19 Predicts SVR: IL-28B
Polymorphism rs12979860
IL28B gene IFN Lambda-3 gene
3 k
b
19q13.13
Ge D, et al. Nature. 2009;461:399-401.
Chromosome 19 graphic courtesy of Oak Ridge National Laboratory. Available at:
http://www.ornl.gov/sci/techresources/meetings/ecr2/olsen.gif. Accessed on: October 21, 2009.
![Page 22: Title slide Genetics/Genomics in Hepatitis and Liver … · Genetics/Genomics in Hepatitis and Liver Disease ... The Next Step after the Human Genome Project ... Simple Mendelian](https://reader031.fdocuments.us/reader031/viewer/2022022608/5b891de37f8b9abf5c8cffb2/html5/thumbnails/22.jpg)
Ge et al, Nature, 2009
IL-28B CC genotype is associated
with SVR
![Page 23: Title slide Genetics/Genomics in Hepatitis and Liver … · Genetics/Genomics in Hepatitis and Liver Disease ... The Next Step after the Human Genome Project ... Simple Mendelian](https://reader031.fdocuments.us/reader031/viewer/2022022608/5b891de37f8b9abf5c8cffb2/html5/thumbnails/23.jpg)
Evolving Paradigms for Predicting Response to IFN-based
Rx for HCV – Genetics emerges!
1995-2000
• Genotype 2/3
• No advanced fibrosis
• Low viral load
• Younger age
• <40 years
• Female
• Weight
2007-2011
• Lack of steatosis
• No insulin resistance
• Adherence
• Rapid viral response (RVR)
• Ribavirin dosage
• Race/ethnicity
• IL-28B
• Anemia
McHutchison JG, et al. N Engl J Med. 2009. Manns MP, et al. Lancet. 2001
Patton HM, et al. J Hepatol. 2004; Poynard T, et al. Lancet. 1998.
2011-present
• Race/ethnicity
• low viral load
• absence of cirrhosis
• statin use
• IL-28B
• Genotype 1a/1b
• On treatment viral response
Lead-in
eRVR
![Page 24: Title slide Genetics/Genomics in Hepatitis and Liver … · Genetics/Genomics in Hepatitis and Liver Disease ... The Next Step after the Human Genome Project ... Simple Mendelian](https://reader031.fdocuments.us/reader031/viewer/2022022608/5b891de37f8b9abf5c8cffb2/html5/thumbnails/24.jpg)
Impact of Genomics on HCV Progression
Host, not Viral Factors Correlate with
Fibrosis Progression in HCV
• No correlation between either HCV viral load or genotype and fibrosis progression
• Gender, alcohol use, and other risks contribute, but don’t explain all the differences
• SNPs may correlate with fibrosis progression in humans
![Page 25: Title slide Genetics/Genomics in Hepatitis and Liver … · Genetics/Genomics in Hepatitis and Liver Disease ... The Next Step after the Human Genome Project ... Simple Mendelian](https://reader031.fdocuments.us/reader031/viewer/2022022608/5b891de37f8b9abf5c8cffb2/html5/thumbnails/25.jpg)
0
1
2
3
4
0 10 20 30 40 50
F METAVIR
Duration in years
Rapid
Intermediate
Slow fibroser
Poynard et al. Lancet 1997; 349: 825
N=1157
Patients with HCV have Variable
Fibrosis Progression
![Page 26: Title slide Genetics/Genomics in Hepatitis and Liver … · Genetics/Genomics in Hepatitis and Liver Disease ... The Next Step after the Human Genome Project ... Simple Mendelian](https://reader031.fdocuments.us/reader031/viewer/2022022608/5b891de37f8b9abf5c8cffb2/html5/thumbnails/26.jpg)
SNPs Associated with Cirrhosis Risk Score (CRS)
Huang H, et al. Hepatology, 2007
Predictors Public ID Gene (Chr) Risk
Genotype or
Phenotype
P valuea
(Univariate)
ORs (95%CI)
SNP1b AZIN1 (Chr8) GG 0.0002 3.23
(1.76-6.11)
SNP2 rs4986791 TLR4 (Chr9) CC 0.0004 3.11
(1.66-5.81)
SNP3 rs886277 TRPM5 (Chr11) CT, CC 0.0006 2.05
(1.36-3.08)
SNP4 rs2290351 none (Chr15)
242
AG,AA 0.0038 1.86
(1.22-2.82)
SNP5 rs4290029 none (Chr1) GG 0.0001 2.35
(1.52-3.63)
SNP6 rs17740066 none (Chr3) AG, AA 0.0014 2.76
(1.48-5.15)
SNP7 rs2878771 AQP2 (Chr12) GG 0.0003 2.17
(1.42-3.30)
![Page 27: Title slide Genetics/Genomics in Hepatitis and Liver … · Genetics/Genomics in Hepatitis and Liver Disease ... The Next Step after the Human Genome Project ... Simple Mendelian](https://reader031.fdocuments.us/reader031/viewer/2022022608/5b891de37f8b9abf5c8cffb2/html5/thumbnails/27.jpg)
HCV patients
Low
Medium
High
Equal Stratification of Risk in Placebo
and Rx Groups is Critical
• Low, medium and high refer to fibrosis stage or progression rate
Placebo Group
Rx Group
Unequal
stratification!
![Page 28: Title slide Genetics/Genomics in Hepatitis and Liver … · Genetics/Genomics in Hepatitis and Liver Disease ... The Next Step after the Human Genome Project ... Simple Mendelian](https://reader031.fdocuments.us/reader031/viewer/2022022608/5b891de37f8b9abf5c8cffb2/html5/thumbnails/28.jpg)
HCV patients
Low
Medium
High
Selection of Patients with High Fibrosis Progression Rate will Optimize
Antifibrotic Clinical Trials
• Low, medium and high refer to fibrosis progression rate
Placebo Group
Rx Group
![Page 29: Title slide Genetics/Genomics in Hepatitis and Liver … · Genetics/Genomics in Hepatitis and Liver Disease ... The Next Step after the Human Genome Project ... Simple Mendelian](https://reader031.fdocuments.us/reader031/viewer/2022022608/5b891de37f8b9abf5c8cffb2/html5/thumbnails/29.jpg)
SNPs Associated with Fibrosis Risk -
Implications
1. Potential to predict disease progression and
refine Rx
2. Possible correlation of liver fibrosis SNPs with
progression in other organs, including kidney,
lung, & pancreas
3. Discovery of new genes mechanistically linked to
pathogenesis
![Page 30: Title slide Genetics/Genomics in Hepatitis and Liver … · Genetics/Genomics in Hepatitis and Liver Disease ... The Next Step after the Human Genome Project ... Simple Mendelian](https://reader031.fdocuments.us/reader031/viewer/2022022608/5b891de37f8b9abf5c8cffb2/html5/thumbnails/30.jpg)
Using SNP information to Uncover New Biology
Huang H, et al. Hepatology, 2007
Predictors Public ID Gene (Chr) Risk
Genotype or
Phenotype
P valuea
(Univariate)
ORs (95%CI)
SNP1b AZIN1 (Chr8) GG 0.0002 3.23
(1.76-6.11)
SNP2 rs4986791 TLR4 (Chr9) CC 0.0004 3.11
(1.66-5.81)
SNP3 rs886277 TRPM5 (Chr11) CT, CC 0.0006 2.05
(1.36-3.08)
SNP4 rs2290351 none (Chr15)
242
AG,AA 0.0038 1.86
(1.22-2.82)
SNP5 rs4290029 none (Chr1) GG 0.0001 2.35
(1.52-3.63)
SNP6 rs17740066 none (Chr3) AG, AA 0.0014 2.76
(1.48-5.15)
SNP7 rs2878771 AQP2 (Chr12) GG 0.0003 2.17
(1.42-3.30)
![Page 31: Title slide Genetics/Genomics in Hepatitis and Liver … · Genetics/Genomics in Hepatitis and Liver Disease ... The Next Step after the Human Genome Project ... Simple Mendelian](https://reader031.fdocuments.us/reader031/viewer/2022022608/5b891de37f8b9abf5c8cffb2/html5/thumbnails/31.jpg)
Toll-Like Receptors (TLRs)
Beutler B. Nature 2004,430(6996):257-63.
• A family of mammalian
transmembrane pattern-recognition
receptors
• Recognize structural components
unique to bacteria, fungi and
viruses
• Signal and activate inflammatory
responses
LPS
TLR4
• Two well-known SNPs
correlate with SLOWER fibrosis
progression:
• Asp299Gly - “299”
• Thr399Ile - “399”
![Page 32: Title slide Genetics/Genomics in Hepatitis and Liver … · Genetics/Genomics in Hepatitis and Liver Disease ... The Next Step after the Human Genome Project ... Simple Mendelian](https://reader031.fdocuments.us/reader031/viewer/2022022608/5b891de37f8b9abf5c8cffb2/html5/thumbnails/32.jpg)
Prediction:
Genomics Will “Personalize” Health Care
![Page 33: Title slide Genetics/Genomics in Hepatitis and Liver … · Genetics/Genomics in Hepatitis and Liver Disease ... The Next Step after the Human Genome Project ... Simple Mendelian](https://reader031.fdocuments.us/reader031/viewer/2022022608/5b891de37f8b9abf5c8cffb2/html5/thumbnails/33.jpg)
What Is Personalized Medicine?
• Use medications and other
treatments that would work
best for each individual
• Avoid medications that would
cause an individual to have
adverse side effects
• Predict which illnesses an
individual was likely to get
and design a personalized
health care plan to prevent or
detect these diseases early
New York Times Magazine, Sunday, November 6, 2005.
![Page 34: Title slide Genetics/Genomics in Hepatitis and Liver … · Genetics/Genomics in Hepatitis and Liver Disease ... The Next Step after the Human Genome Project ... Simple Mendelian](https://reader031.fdocuments.us/reader031/viewer/2022022608/5b891de37f8b9abf5c8cffb2/html5/thumbnails/34.jpg)
Genetic Differences in Drug Metabolism The First Frontier of Personalized Medicine
“Pharmacogenomics”
• To determine efficacy and dosing of
drugs
• To predict risk of toxicity
![Page 35: Title slide Genetics/Genomics in Hepatitis and Liver … · Genetics/Genomics in Hepatitis and Liver Disease ... The Next Step after the Human Genome Project ... Simple Mendelian](https://reader031.fdocuments.us/reader031/viewer/2022022608/5b891de37f8b9abf5c8cffb2/html5/thumbnails/35.jpg)
Personalized Medicine -
Genetic Definition of Subpopulations
With Different Response Profiles
![Page 36: Title slide Genetics/Genomics in Hepatitis and Liver … · Genetics/Genomics in Hepatitis and Liver Disease ... The Next Step after the Human Genome Project ... Simple Mendelian](https://reader031.fdocuments.us/reader031/viewer/2022022608/5b891de37f8b9abf5c8cffb2/html5/thumbnails/36.jpg)
Drug Induced Liver Injury Network (DILIN)
https://dilin.dcri.duke.edu/
![Page 37: Title slide Genetics/Genomics in Hepatitis and Liver … · Genetics/Genomics in Hepatitis and Liver Disease ... The Next Step after the Human Genome Project ... Simple Mendelian](https://reader031.fdocuments.us/reader031/viewer/2022022608/5b891de37f8b9abf5c8cffb2/html5/thumbnails/37.jpg)
Summary & Predictions –
Genetics and Genomics in Hepatitis and Liver Disease
• Genomic information will profoundly improve our ability to predict:
Disease risk and progression rates
Response to therapies
Drug-related liver toxicities
• The demand for integrating genomic information will require:
‘Big data’ platforms to integrate genomic and EMR data
Software systems to insert decision-support guidance based on these data at
the point-of-care
• The need to assimilate these approaches will be driven by:
Insurers who seek to prevent disease and optimize Rx to reduce costs
Entrepreneurs and businesses with novel IT and technology solutions
Academic medical centers who can ‘ride the wave’ (e.g. Mount Sinai)
The public, and patients & their families, NOT by providers