it essentials for a personalized genomic medicine …days 8 - 90 days 3 - 7 aggregated results for...

IT Essentials for a Personalized Genomic Medicine Era

Feb 15-16th, 2011 D.C.

Peter J. Tonellato, PhDBeth Israel Deaconess Medical Center

Harvard Medical School

IT Personalized Medicine

1. IT Infrastructure supporting International Smart Health Informatics

2. Two Test (Simulation) Scenarios

- Whole Genomes to Actionable Health Information

- International Comparative Effectiveness

3. Future Issues

Translational Research

Round holes arise in clinical setting

Square Pegs derived from basic research

Translation emerges from Commercial R&D and Regulatory Approval process followed by clinical implementation

Clinical Enterprise Research Enterprise

Translational Research


Translation

Simulations and Predictions

LPM

Clouded Translational Research


Translation

Simulations and Predictions

LPM


Translation: Research

InSilico Cloud ComputingLPM

Translation: Clinical

The goal of the LPM is systematically translate research into the clinic






3. Future Issues

Representative Example:The Patient’s Genome

Opportunity (“round hole”): Patient’s genomic variants improve prediction and prevention of ADR.

Scientific Response (“square peg”): NGS (~$5K-20K) whole genome data set. Collection of data is unwieldy; too large to be managed and interpreted in the clinic; ; and should not be incorporated into the current versions of Electronic Health Record.

Clinical Solution (“rounder peg”): Process whole genome into annotated variants suitable for EHR, clinical use, physician interpretation.

Input data(FASTQ)

Clean Reads

GQ Read Cleaning

Trim low quality bases (Phred-like

quality <=11) from both ends

Remove reads >=10 low quality ba

ses (Phred-like quality

<=11) in first 28 bp

Remove reads with Ns in them

Remove reads with length <=28 bp

“Unique”

alignments

Other alignments

Unmapped reads

Annotated variant DB

Basic variant DB

GQ Read Mapping

Best fit alignment (GASSST)

Very fast with mismatches and indels

Multi-core and multi-threaded

Up to 8 mismatches / indels per read

Also works in colorspace (Solid)

Unique alignment means only one

best alignment

GQ Variant Calling

Variant base Phred-like quality >=20

Flanking bases Phred-like quality >=15

Distance variant to edge alignment >=3

Identical alignment only counted once

At least 10 independent reads (passing

these tests) needed to confirm an allele

Reference alleles called as well

GQ Variant Annotation

Refseq genes, exons, CDS

dbSNP, repeats, OMIM genes,

pharmGkb

Variant impact prediction (sense,

nonsense, frameshift, premature stop,

UTR, amino acid indels, intron-exon

boundary distortion)

GenomeQuest sequence

database

Highly compressed

binary format

Contains sequences and

annotation

Searchable (indexed)

Create any text output

(templated)

Accessible through web

and efficient scripting

API

GenomeQuest alignment

database

Highly compressed

binary format (48 bytes

per alignment)

Contains alignments,

scores, and references

to sequences and

annotation

Searchable (indexed)

Create any text output

(templated)

Accessible through web

and efficient scripting

API

GenomeQuest Whole Genome Analysis Pipeline

Example GQ Annotated Record

Associated disease/phenotype:Warfarin resistance

Warfarin Dosing – African Individual

Warfarin Dosing Algorithm (Gage Group)Dose = exp*0.9751 − 0.3238 × v(y) + (0.4317 × BSA) - 0.4008

× c_3(y) − (0.00745 × age) − 0.2066 × c_2(y) + (0.2029 × target INR) − (0.2538 x amiodarone) + (0.0922 ×smokes) - (0.0901 × African-American race) + (0.0664 × DVT/PE)]{ 0 if VKORC1 -1639 genotype = G/G

v(y) = { 1 if VKORC1 -1639 genotype = G/A{ 2 if VKORC1 -1639 genotype = A/A{ 0 if CYP2C9*2 genotype = C/C

c_2(y) = { 1 if CYP2C9*2 genotype = C/T{ 2 if CYP2C9*2 genotype = T/T{ 0 if CYP2C9*3 genotype = A/A

c_3(y) = { 1 if CYP2C9*3 genotype = A/C{ 2 if CYP2C9*3 genotype = C/C

Gage B, Eby C, Johnson J, Deych E, Rieder M, Ridker P, et al. Use of Pharmacogenetic and Clinical Factors to Predict the Therapeutic Dose of Warfarin. Clin.Pharmacol.Ther. 2008 Feb 27.

Patient DataAge: 40*

Gender: MRace: AfricanHeight: 70”*

Weight: 140 lbs*

Smoker: No*

Amiodarone Use: No*

DVT: No*

Target INR: 2.5* - Inferred Values

Genotype

CYP2C9*2 C/C

CYP2C9*3 A/A

VKORC1(-1639) G/G

Recommended Warfarin Dose:

7.0 mg

Current guidelines recommend:

5.0 mg

IT-Genome Technologies: ROI?

Cost of… Today Future (IWGM/GQ)

Sequencing CF - ACMG/ACOG Mutation Panel: $250

LabCorp CYP2C9/VKORC1: $500

Myriad BRACAnalysis: $3,120

$5,000

Computational Reduction $0 $2,000Integration into EMR $1,000 $1,000Seeing Patient $4,500 $4,500Interpretation $2,000 $2,000Clinical Action $1,500 $1,500Total Cost of Care $12,970 $16,000Reimbursement $12,970 $9,000






3. Future Issues

Clinical avatars are statistical representations of actual populations

Clinical avatar records – used as input to the clinical trial simulation framework

Bayesian Model Simulation Framework

Bayesian network produces statistically accurate representations actual people

Age

Gender

Race

CYP2C9

VKORC1

DVT

Height

Smoker

AMI

Weight

Network dependencies means we won’t have unrealistic avatars

Short and fat

Tall and skinny

Ken from Toy Story 3

Clinical trial simulation framework

Clinical Avatars

Initial Dose

INR Prediction

Outcome Metric

Dose Adj. Protocol

30

–9

0 d

ays

Simulate populations based on characteristics such as genotype, age, and race

1. GAGE_DOSE = exp(0.98 - (0.32*VKORC1) + (0.43*BSA) - (0.40*CYP2C9) -(0.0075*AGE) - (0.20*CYP2C92) + (0.20*TINR) + (0.09*SMOKER) - (0.09*RACE) + (0.07*DVT) - (0.25*AMI))

2. ANDERSON_DOSE = (1.64 + exp(3.984 + CYP2C9- VKORC1 + AGE*(-0.009) + GENDER + WEIGHT*(0.003)))/7

2-compartment model with 1st

order input & output [Hamberg 2007]

AD 1 2

K21

K12K10

Ka

1. Coumagen trial2. Wilson, 20073. Fixed percent adjustment

Time in therapeutic range (TTR)

1 2 3 4 5 6 7 8 9 10

Days

2

3

Time

INR

Example of the Couma-Gen clinical trial protocol complexity

Days 1 - 2

10 mg daily dose

Days 8 - 90

Days 3 - 7

Aggregated results for 100 clinical avatars

Mohamed Abouelhoda,

Professor of Information Technology

Nile University

Health Cloud Workshop, Dec, 2010

+100 Participants (Registration

website shut down in 1 day)

Abouelhoda-Wall-Tonellato

US-Egypt Joint Board on Scientific and Technological Cooperation:

Collaborative Research Grant Proposal

Clouded Optimization of NGW WGA

Milwaukee & Cairo Clinical AvatarsSimulate

Milwaukee

County*(n=930,261)

and

Cairo#

(n=7,137,218)

Analyze

Results *Wisconsin Interactive Statistics on Health (WISH). Wisconsin Department of Health Services; 2009.

#Egypt Demographic and Health Survey; 2008. World Health Organization (WHO); 2007.

Predict

Initial

Dose

Differences in Warfarin Dosing (age ≥ 25)






3. Future Issues

Apoptotic Signaling Pathway

PARP Inhibitor Treatment

RNA-SEQ Gene Expression

Profile

MicroRNA Expression Profile

DNA MethylationProfile

DNA-SEQ

Status of BRCA mutations contributing to homologous recombination

Square peg ===> round hole

LPM

Understanding

the Structure of

Genomes

Understanding

the Biology of

Genomes

Understanding

the Biology of

Disease

Advancing

the Science of

Medicine

Improving the

Effectiveness

of Healthcare

1990-2003Human Genome Project

2004-2010

2011-2020

Beyond 2020

Genomic Accomplishments: Base Pairs to Bedside

Eric Green,

Director, NHGRI

Nature, Feb, 2011

IT Personalized MedicineFuture Considerations

1. IT infrastructure supports ubiquitous smart health apps

2. Rapidly emerging biotechnology (NGS) uses the same infrastructure

3. The marriage of IT and wireless devices promises to deliver unprecedented healthcare information

4. Effective (cost, health outcome, implementation) use of these technologies requires mathematical modeling and simulations

IT Essentials for a Personalized Genomic Medicine Era

Feb 15-16th, 2011 D.C.

Peter J. Tonellato, PhDBeth Israel Deaconess Medical Center

Harvard Medical School

it essentials for a personalized genomic medicine …days 8 - 90 days 3 - 7 aggregated results for...

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