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Understanding the Development and
Progression of Disease.
Michael N. Liebman, PhDChief Scientific Officer
Windber Research Institute
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Overview
Clinical Breast Care Project (CBCP) Windber Research Institute Data, Information and KnowledgeSystems BiologyDefining Translational ResearchUnderstanding the Question(s)
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Clinical Breast Care ProjectCreation of CBCP reference database– 10,000 breast disease patients/year
• Ethnic diversity; “transient• Equal access to health care for breast disease• All acquired under SINGLE PROTOCOL• All reviewed by a SINGLE PATHOLOGIST
– Tissue, serum, lymph nodes (>14,000 samples)– patient data (500+data fields) – mammograms, 4d-ultrasound, PET/CT, 3T MRI– complementary genomics and proteomics, IHC– Breast cancer vaccine program (her2/neu)
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Windber Research Institute
Founded in 2001, 501( c) (3) corporationGenomic, proteomic and informatics collaboration with WRAMC45 scientists (8 biomedical informaticians)36,000 sq ft facility under constructionFocus on Women’s Health, Cardiovascular Disease, Processes of Aging
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WRI’s Mission
WRI intends to be a catalyst in the creationof the “next-generation” of medicine,integrating basic and clinical research with an emphasis on improving patientcare and the quality of life for the patient and their family.
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Gap
INFORMATION
KNOWLEDGEGAP
GAP
GAP
TIME
AM
OU
NT
DATA
CLINICAL UTILITY
KNOWLEDGE
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Systems Biology(Personalized Medicine)
Genomics Proteomics CGHMetab-olomics
Patient
Physiology
-omics
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Bottom Up Approach
Genomics Proteomics CGHMetab-olomics
Patient
Physiology
????
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Top Down Approach(Personalized Disease)
Genomics Proteomics CGHMetab-olomics
Patient
Physiology
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Translational Medicine
ClinicalPractice
“Bedside”
TrainingJob Function“Language”
CultureResponsibilitiesBasic
Research“Bench”
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“Discovery consists in seeing whatEveryone else has seen and thinkingWhat no one else has thought”
A. Szent-Gyorgi
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1. Modeling Disease
Disease as a State vs Disease as a ProcessBias of PerspectiveTemporal Perspective
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Modeling Disease
Lifestyle + Environment = F(t)
Disease(s){ }Risk(s){ }
| Genotype | Phenotype |
(SNP’s, Expression Data) (Clinical History and Data)
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UMLS Semantic Network
??
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Disease Etiology
Genetic Lifestyle Breast Survival Risk Factors Cancer (Chronic Disease)
DIAGNOSIS
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Pathway of Disease
TreatmentOptions
QualityOf Life
GeneticRisk
EarlyDetection
Patient Stratification
DiseaseStaging
Outcomes
Natural History of Disease Treatment History
Biomarkers
Environment+ Lifestyle
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Phenotype| Genotype | |
PhenotypeTIME
Childhood Diseases
Diabetes
Cardiovascular Disease
Smoking
Overweight
2nd Hand Smoke
Menarche
Breast Cancer(Age 48)Natural History ?
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Longitudinal Interactionsin Breast Cancer
Identify Environmental FactorsQuantify Exposure– When ?– How Long ?– How Much ?
Extract Dosing ModelCompare with Stages of Biological Development
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Lifestyle Factors
5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95
AGE
Alcohol
5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95
AGE
Smoking
5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95
AGE
Obesity
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2. Genetics and Disease
Genetic Pre-Disposition– < 10 % of all breast cancers– Not all BRCA1 and BRCA2 mutations
result in breast cancer- Modifier genes?- Lifestyle or environmental factors?- Pedigree Analysis
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Pedigree (modified)Ti
me Polio Vaccine
Menopause
Influenza
MeaslesInfluenza
1940
1950
1960
1970
Prostate Cancer
1980
1990
2000
PSA
DES
Influenza Pandemic 1918
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3. Aging and Disease
Processes of Aging vs Disease ProcessesOngoing Breast DevelopmentSame Disease : Different Host?Text Data-mining Approaches
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Disease vs Aging
Menopause
HormoneReplacement Heart Disease
Breast Cancer
Ovarian Cancer
Osteoporosis
Alzheimer’s
<50 years>
Menarche
Child-bearing
Peri-menopause
{ {Aging Disease
Quality of Life
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Breast Development
Menarche
Child-bearingPeri-menopause
CumulativeDevelopment
Lactation
Menopause
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Ontology: Breast DevelopmentParous
Terminal Buds
Buds Lobes Ducts
Neo- Menarche Pregnancy Lactation Peri Menop Postnatal menop Menop
Buds Lobes
Puberty
Terminal BudsHuman Mouse?
NulliParous
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SPSS – LexiMine and Clementine
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Puberty: •Two hormones – estrogen and progesterone signal the
development of the glandular breast tissue.•In female estrogen acts on mesenchymal cells to stimulate further
development.•The gland increases in size due to deposition of interlobular fat.•The ducts extend and branch into the expanding stroma.•The epithelial cell proliferation and basement membrane
remodeling is controlled by interactions between theepithelium and the intra-lobular hormone sensitive zone offibroblasts.
•The smallest ducts, the intra-lobular ducts, end in the epithelial budswhich are the prospective secretory alveoli.
•Breast ducts begin to grow and this growth continues until menstruation begins.
Production of: Stroma, mesenchymal cells, epithelial cells
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Reality of DiseaseDNA RNA Amino Acids
Genes
Tissues Cells OrganellesProcesses: Tissue generation; Inflammation….
Pathways
Gen
e O
ntol
ogy Enzymes Substrates Co-Factors
Proteins
Physiological Development
Dis
ease
Prog
ress
ion
(tim
e)
Physiological Systems
(time)
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4. Stratifying Disease
Tumor StagingT,M,N tumor scoringAnalysis of Outcomes
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Cancer Progression
localized regional metastatic
0 I IIA IIB IIIA IIIB IV
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Tumor Progression
0I
IIA
IIB
IIIA
IIIB
IV
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Tumor StagingStage 0(Tis, N0, M0)
Stage IIA(T0, N1, M0 ); (T1,* N1,** M0); (T2, N0, M0) [*T1 includes T1mic ][**The prognosis of patients with pN1a disease is similar to that of patients with pN0 disease] Stage IIB(T2, N1, M0) ; (T3, N0, M0)Stage IIIA
(T0, N2, M0); (T1,* N2, M0); (T2, N2, M0); (T3, N1, M0); (T3, N2, M0)[*T1 includes T1mic ]
Stage IIIB(T4, Any N, M0) ; (Any T, N3, M0)Stage IV(Any T, Any N, M1)
Stage I(T1,* N0, M0) ; [*T1 includes T1mic]
Stage IIIC(Any T, N3, Any M)
10/10/02
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(T, M, N) Information Content
T
M
IIa
GOOD
POOR
N
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Data Integration
Data Warehouse Model– Teradata Oracle
Cimarron’s Scierra LIMS– Amersham LWS
Creation of CLWS
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A Patient is:
Patient
Family History…… NurseGenomics…………. Genetic Couns.Demographics…….EpidemiologistEnvironment………Envir. ScientistLifestyle……………Social ScientistClinical History….. PhysicianTherapeutic History.. PharmacistTissue Samples……PathologistCost of Treatment…InsurerQuality of Life…….Patient……….
A Patient is a Mother, Sister, Wife, Daughter…..
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Modular Data ModelTissue/sample repository (T/S)Outcomes (O)Genomics (G)Biomarkers (B)Co-morbidities (C)Proteomics (Pr)
Swappable based on Disease
Socio-demographics(SD)Reproductive History(RH)Family History (FH)Lifestyle/exposures (LE)Clinical history (CH)Pathology report (P)
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Conclusions
Personalized Disease will improve Patient Care, Today; Personalized Medicine, TomorrowDisease is a Process, not a StateTranslational Medicine must be both:– Bedside-to-bench, and– Bench-to-bedside
The processes of aging are critical:– For accurate diagnosis of the patient– For converting breast cancer to a chronic disease
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AcknowledgementsWindber Research InstituteJoyce Murtha Breast Care CenterWalter Reed Army Medical CenterImmunology Research CenterMalcolm Grow Medical CenterLandstuhl Medical CenterHenry Jackson FoundationUSUHSMRMC-TATRCMilitary Cancer Institute
Patients, Personnel and Family!