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Transcript of Disease s Anatom y Genes Physiolog y Diseases Physiology Anatomy Genes Diseases Medical Informatics...
DiseasesDiseasesDiseases
DiseasesDiseasesDiseases
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Diseases
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Medical Informatics
Bioinformatics
Novel relationships & Deeper insights
04/19/23
Mining Bio-Medical Mountains
How Computer Science can help Biomedical Research and Health
Sciences
& YOU
Anil JeggaDivision of Biomedical Informatics,
Cincinnati Children’s Hospital Medical Center (CCHMC)Department of Pediatrics, University of Cincinnati
http://[email protected]
AcknowledgementBiomedical
Engineering/Bioinformatics• Jing Chen• Sivakumar Gowrisankar• Vivek KaimalComputer Science• Amit Sinha• Mrunal Deshmukh• Divya SardanaElectrical Engineering• Nishanth Vepachedu
Medical Informatics Bioinformatics & the “omes
Patient Records
Patient Records
Disease Database
Disease Database→Name→Synonyms→Related/Similar Diseases→Subtypes→Etiology →Predisposing Causes→Pathogenesis→Molecular Basis→Population Genetics→Clinical findings→System(s) involved→Lesions →Diagnosis→Prognosis→Treatment→Clinical Trials……
PubMed
Clinical Trials
Clinical Trials
Two Separate Worlds…..
With Some Data Exchange…
Genome
Transcriptome
miRNAome
Interactome
Metabolome
Physiome
Regulome Variome
Pathome Ph
arm
acog
en
om
e
OMIMClinical
Synopsis
Disease
World
382 “omes” so far………
and there is “UNKNOME” too - genes with no function knownhttp://omics.org/index.php/Alphabetically_ordered_list_of_omics
Proteome
now…. The number 1 FAQHow much biology should I
know??No simple or straight-forward answer…
unfortunately!But the mantra is:
Interact routinely with biologists
ORWork with the biologists or the
biological data
But I want to learn some basics…1. http://www.ncbi.nlm.nih.gov/Education2. http://www.ebi.ac.uk/2can/3. http://www.genome.gov/Education/4. http://genomics.energy.gov/Books1. Introduction to Bioinformatics by Teresa Attwood, David Parry-
Smith2. A Primer of Genome Science by Gibson G and Muse SV3. Bioinformatics: A Practical Guide to the Analysis of Genes and
Proteins, Second Edition by Andreas D. Baxevanis, B. F. Francis Ouellette
4. Algorithms on Strings, Trees, and Sequences: Computer Science and Computational Biology by Dan Gusfield
5. Bioinformatics: Sequence and Genome Analysis by David W. Mount
6. Discovering Genomics, Proteomics, and Bioinformatics by A. Malcolm Campbell and Laurie J. Heyer
And the other FAQs….
1. What bioinformatics topics are closest to computer science?
2. Should computer science departments involve themselves in preparing their graduates for careers in bioinformatics?
3. And if so, what topics should they cover?
4. And how much biology should they be taught?
5. Lastly, how much effort should be expended in re-directing computer scientists to do work in bioinformatics?
Cohen, 2005; Communications of the ACM
Issues to be considered……..1. Computer science Vs molecular biology
– Subject & Scientists - Cultural differences
2. Current goals of molecular biology, genomics (or biomedical research in a broader sense)
3. Data types used in bioinformatics or genomics
4. Areas within computer science of interest to biologists
5. Bioinformatics research - Employment opportunities
Biological Challenges - Computer Engineers
• Post-genomic Era and the goal of bio-medicine– to develop a quantitative understanding of how
living things are built from the genome that encodes them.
• Deciphering the genome code– Identifying unknown genes and assigning function
by computational analysis of genomic sequence– Identifying the regulatory mechanisms– Identifying their role in normal development/states
vs disease states
• Data Deluge: exponential growth of data silos and different data types– Human-computer interaction specialists need
to work closely with academic and clinical biomedical researchers to not only manage the data deluge but to convert information into knowledge.
• Biological data is very complex and interlinked!– Creating information systems that allow
biologists to seamlessly follow these links without getting lost in a sea of information - a huge opportunity for computer scientists.
Biological Challenges - Computer Engineers
• Networks, networks, and networks!– Each gene in the genome is not an
independent entity. Multiple genes interact to perform a specific function.
– Environmental influences – Genotype-environment interaction
– Integrating genomic and biochemical data together into quantitative and predictive models of biochemistry and physiology
– Computer scientists, mathematicians, and statisticians will ALL be an integral and critical part of this effort.
Biological Challenges - Computer EngineersA major goal in
molecular biology is Functional Genomics
– Study of the relationships among genes in DNA & their function – in normal and disease states
Informatics – Biologists’ Expectations
• Representation, Organization, Manipulation, Distribution, Maintenance, and Use of information, particularly in digital form.
• Functional aspect of bioinformatics: Representation, Storage, and Distribution of data.– Intelligent design of data formats and
databases– Creation of tools to query those databases– Development of user interfaces or
visualizations that bring together different tools to allow the user to ask complex questions or put forth testable hypotheses.
• Developing analytical tools to discover knowledge in data– Levels at biological information is used:
•comparing sequences – predict function of a newly discovered gene
•breaking down known 3D protein structures into bits to find patterns that can help predict how the protein folds
•modeling how proteins and metabolites in a cell work together to make the cell function…….
Informatics – Biologists’ Expectations
Finally….What does informatics mean to biologists?
The ultimate goal of analytical bioinformaticians is to develop predictive methods that allow biomedical researchers and scientists to model the function and phenotype of an organism based only on its genomic sequence. This is a grand goal, and one that will be approached only in small steps, by many scientists from different but allied disciplines working cohesively.
Biology – Data StructuresFour broad categories:
1.Strings: To represent DNA, RNA, amino acid sequences of proteins
2.Trees: To represent the evolution of various organisms (Taxonomy) or structured knowledge (Ontologies)
3.Sets of 3D points and their linkages: To represent protein structures
4.Graphs: To represent metabolic, regulatory, and signaling networks or pathways
Biology – Data StructuresBiologists are also interested in1.Substrings2.Subtrees3.Subsets of points and linkages, and 4.Subgraphs.
Beware: Biological data is often characterized by huge size, the presence of laboratory errors (noise), duplication, and sometimes unreliability.
Support Complex Queries – A typical demand
• Get me all genes involved in or associated with brain development that are differentially expressed in the Central Nervous System.
• Get me all genes involved in brain development in human and mouse that also show iron ion binding activity.
• For this set of genes, what aspects of function and/or cellular localization do they share?
• For this set of genes, what mutations are reported to cause pathological conditions?
Model Organism Databases: Common Issues
• Heterogeneous Data Sets - Data Integration– From Genotype to Phenotype– Experimental and Consensus Views
• Incorporation of Large Datasets– Whole genome annotation pipelines– Large scale mutagenesis/variation projects
(dbSNP)
• Computational vs. Literature-based Data Collection and Evaluation (MedLine)
• Data Mining– extraction of new knowledge– testable hypotheses (Hypothesis Generation)
Bioinformatic Data-1978 to present
• DNA sequence• Gene expression• Protein expression• Protein Structure• Genome mapping• SNPs & Mutations
• Metabolic networks• Regulatory networks• Trait mapping• Gene function
analysis• Scientific literature• and others………..
Human Genome Project – Data Deluge
Database name Records
Nucleotide 12,427,463
Protein 419,759
Structure 11,232
Genome Sequences
75
Popset 21,010
SNP 11,751,216
3D Domains 41,857
Domains 19
GEO Datasets 5,036
GEO Expressions 16,246,778
UniGene 123,777
UniSTS 323,773
PubMed Central 4,278
HomoloGene 19,520
Taxonomy 1
No. of Human Gene Records currently in NCBI: 29413 (excluding pseudogenes, mitochondrial genes and obsolete records).
Includes ~460 microRNAs
NCBI Human Genome Statistics – as on February12, 2008
The Gene Expression Data Deluge
Till 2000: 413 papers on microarray!
YearPubMed Articles
2001 834
2002 1557
2003 2421
2004 3508
2005 4400
2006 4824
2007 5108
2008 647…
Problems Deluge!Allison DB, Cui X, Page GP, Sabripour M. 2006. Microarray data analysis: from disarray to consolidation and consensus. Nat Rev Genet. 7(1): 55-65.
• 3 scientific journals in 1750
• Now - >120,000 scientific journals!
• >500,000 medical articles/year
• >4,000,000 scientific articles/year
• >16 million abstracts in PubMed derived from >32,500 journals
Information Deluge…..
A researcher would have to scan 130 different journals and read 27 papers per day to follow a single disease, such as breast cancer (Baasiri et al., 1999 Oncogene 18: 7958-7965).
•Accelerin•Antiquitin•Bang Senseless•Bride of Sevenless•Christmas Factor•Cockeye•Crack•Draculin•Dickie’s small eye
Disease names• Mobius Syndrome with
Poland’s Anomaly• Werner’s syndrome• Down’s syndrome• Angelman’s syndrome• Creutzfeld-Jacob
disease
•Draculin•Fidgetin•Gleeful•Knobhead•Lunatic Fringe•Mortalin•Orphanin•Profilactin•Sonic Hedgehog
Data-driven Problems…..
Gene Nomenclature
• How to name or describe proteins, genes, drugs, diseases and conditions consistently and coherently?
• How to ascribe and name a function, process or location consistently?
• How to describe interactions, partners, reactions and complexes?
• Develop/Use controlled or restricted vocabularies (IUPAC-like naming conventions, HGNC, MGI, UMLS, etc.)
• Create/Use thesauruses, central repositories or synonym lists (MeSH, UMLS, etc.)
• Work towards synoptic reporting and structured abstracting
Some Solutions
1. Generally, the names refer to some feature of the mutant phenotype
2. Dickie’s small eye (Thieler et al., 1978, Anat Embryol (Berl), 155: 81-86) is now Pax6
3. Gleeful: "This gene encodes a C2H2 zinc finger transcription factor with high sequence similarity to vertebrate Gli proteins, so we have named the gene gleeful (Gfl)." (Furlong et al., 2001, Science 293: 1632)
What’s in a name!Rose is a rose is a rose is a rose!
Rose is a rose is a rose is a rose….. Not Really!
Image Sources: Somewhere from the internet…
What is a cell?
• any small compartment
• (biology) the basic structural and functional unit of all organisms; they may exist as independent units of life (as in monads) or may form colonies or tissues as in higher plants and animals
• a device that delivers an electric current as a result of chemical reaction
• a small unit serving as part of or as the nucleus of a larger political movement
• cellular telephone: a hand-held mobile radiotelephone for use in an area divided into small sections, each with its own short-range transmitter/receiver
• small room in which a monk or nun lives
• a room where a prisoner is kept
Foundation Model Explorer
Semantic Groups, Types and Concepts:
• Semantic Group Biology – Semantic Type Cell
• Semantic Groups Object OR Devices – Semantic Types Manufactured Device or Electrical Device or Communication Device
• Semantic Group Organization – Semantic Type Political Group
Hepatocellular Carcinoma
CTNNB1
MET
TP53
1. COLORECTAL CANCER [3-BP DEL, SER45DEL]2. COLORECTAL CANCER [SER33TYR]3. PILOMATRICOMA, SOMATIC [SER33TYR]4. HEPATOBLASTOMA, SOMATIC [THR41ALA]5. DESMOID TUMOR, SOMATIC [THR41ALA]6. PILOMATRICOMA, SOMATIC [ASP32GLY]7. OVARIAN CARCINOMA, ENDOMETRIOID TYPE, SOMATIC [SER37CYS]8. HEPATOCELLULAR CARCINOMA SOMATIC [SER45PHE]9. HEPATOCELLULAR CARCINOMA SOMATIC [SER45PRO]10. MEDULLOBLASTOMA, SOMATIC [SER33PHE]
1. COLORECTAL CANCER [3-BP DEL, SER45DEL]2. COLORECTAL CANCER [SER33TYR]3. PILOMATRICOMA, SOMATIC [SER33TYR]4. HEPATOBLASTOMA, SOMATIC [THR41ALA]5. DESMOID TUMOR, SOMATIC [THR41ALA]6. PILOMATRICOMA, SOMATIC [ASP32GLY]7. OVARIAN CARCINOMA, ENDOMETRIOID TYPE, SOMATIC [SER37CYS]8. HEPATOCELLULAR CARCINOMA SOMATIC [SER45PHE]9. HEPATOCELLULAR CARCINOMA SOMATIC [SER45PRO]10. MEDULLOBLASTOMA, SOMATIC [SER33PHE]
1. HEPATOCELLULAR CARCINOMA SOMATIC [ARG249SER]
1. HEPATOCELLULAR CARCINOMA SOMATIC [ARG249SER]
TP53*
aflatoxin B1, a mycotoxin induces a very specific G-to-T mutation at codon 249 in the tumor suppressor gene p53.
Environmental Effects
Many disease states are complex, because of many genes (alleles & ethnicity, gene families, etc.), environmental effects (life style, exposure, etc.) and the interactions.
The REAL Problems
HEPATOCELLULAR CARCINOMALIVER:
•Hepatocellular carcinoma; •Micronodular cirrhosis; •Subacute progressive viral hepatitis
NEOPLASIA: •Primary liver cancer
CTNNB1
MET
TP53
1. ALK in cardiac myocytes 2. Cell to Cell Adhesion Signaling 3. Inactivation of Gsk3 by AKT causes
accumulation of b-catenin in Alveolar Macrophages
4. Multi-step Regulation of Transcription by Pitx2 5. Presenilin action in Notch and Wnt signaling 6. Trefoil Factors Initiate Mucosal Healing 7. WNT Signaling Pathway
1. ALK in cardiac myocytes 2. Cell to Cell Adhesion Signaling 3. Inactivation of Gsk3 by AKT causes
accumulation of b-catenin in Alveolar Macrophages
4. Multi-step Regulation of Transcription by Pitx2 5. Presenilin action in Notch and Wnt signaling 6. Trefoil Factors Initiate Mucosal Healing 7. WNT Signaling Pathway
1. CBL mediated ligand-induced downregulation of EGF receptors
2. Signaling of Hepatocyte Growth Factor Receptor
1. CBL mediated ligand-induced downregulation of EGF receptors
2. Signaling of Hepatocyte Growth Factor Receptor 1. Estrogen-responsive protein Efp
controls cell cycle and breast tumors growth
2. ATM Signaling Pathway 3. BTG family proteins and cell
cycle regulation 4. Cell Cycle 5. RB Tumor
Suppressor/Checkpoint Signaling in response to DNA damage
6. Regulation of transcriptional activity by PML
7. Regulation of cell cycle progression by Plk3
8. Hypoxia and p53 in the Cardiovascular system
9. p53 Signaling Pathway 10. Apoptotic Signaling in Response
to DNA Damage 11. Role of BRCA1, BRCA2 and ATR
in Cancer Susceptibility….Many More…..
1. Estrogen-responsive protein Efp controls cell cycle and breast tumors growth
2. ATM Signaling Pathway 3. BTG family proteins and cell
cycle regulation 4. Cell Cycle 5. RB Tumor
Suppressor/Checkpoint Signaling in response to DNA damage
6. Regulation of transcriptional activity by PML
7. Regulation of cell cycle progression by Plk3
8. Hypoxia and p53 in the Cardiovascular system
9. p53 Signaling Pathway 10. Apoptotic Signaling in Response
to DNA Damage 11. Role of BRCA1, BRCA2 and ATR
in Cancer Susceptibility….Many More…..
The REAL Problems
1. Link driven federations• Explicit links between databanks.
2. Warehousing• Data is downloaded, filtered,
integrated and stored in a warehouse. Answers to queries are taken from the warehouse.
3. Others….. Semantic Web, etc………
Methods for Integration
1. Creates explicit links between databanks
2. query: get interesting results and use web links to reach related data in other databanks
Examples: NCBI-Entrez, SRS
Link-driven Federations
1.Advantages• complex queries• Fast
2.Disadvantages• require good knowledge• syntax based• terminology problem not solved
Link-driven Federations
Data is downloaded, filtered, integrated and stored in a warehouse. Answers to queries are taken from the warehouse.
Data Warehousing
Advantages1. Good for very-specific,
task-based queries and studies.
2. Since it is custom-built and usually expert-curated, relatively less error-prone.
Disadvantages1. Can become quickly
outdated – needs constant updates.
2. Limited functionality – For e.g., one disease-based or one system-based.
1. Finding similarities among strings2. Detecting certain patterns within
strings3. Finding similarities among parts of
spatial structures (e.g. motifs)4. Constructing trees
• Phylogenetic or taxonomic trees: evolution of an organism
• Ontologies – structured/hierarchical representation of knowledge
5. Classifying new data according to previously clustered sets of annotated data
Algorithms in Bioinformatics
6. Reasoning about microarray data and the corresponding behavior of pathways
7. Predictions of deleterious effects of changes in DNA sequences
8. Computational linguistics: NLP/Text-mining. Published literature or patient records
9. Graph Theory – Gene regulatory networks, functional networks, etc.
10.Visualization and GUIs (networks, application front ends, etc.)
Algorithms in Bioinformatics
Disease Gene Identification and Prioritization
Hypothesis: Majority of genes that impact or cause disease share membership in any of several functional relationships OR Functionally similar or related genes cause similar phenotype.
Functional Similarity – Common/shared•Gene Ontology term•Pathway•Phenotype•Chromosomal location•Expression•Cis regulatory elements (Transcription factor binding sites)•miRNA regulators•Interactions•Other features…..
1. Most of the common diseases are multi-factorial and modified by genetically and mechanistically complex polygenic interactions and environmental factors.
2. High-throughput genome-wide studies like linkage analysis and gene expression profiling, tend to be most useful for classification and characterization but do not provide sufficient information to identify or prioritize specific disease causal genes.
Background, Problems & Issues
3. Since multiple genes are associated with same or similar disease phenotypes, it is reasonable to expect the underlying genes to be functionally related.
4. Such functional relatedness (common pathway, interaction, biological process, etc.) can be exploited to aid in the finding of novel disease genes. For e.g., genetically heterogeneous hereditary diseases such as Hermansky-Pudlak syndrome and Fanconi anaemia have been shown to be caused by mutations in different interacting proteins.
Background, Problems & Issues
1. Direct protein–protein interactions (PPI) are one of the strongest manifestations of a functional relation between genes.
2. Hypothesis: Interacting proteins lead to same or similar disease phenotypes when mutated.
3. Several genetically heterogeneous hereditary diseases are shown to be caused by mutations in different interacting proteins. For e.g. Hermansky-Pudlak syndrome and Fanconi anaemia. Hence, protein–protein interactions might in principle be used to identify potentially interesting disease gene candidates.
PPI - Predicting Disease Genes
Known Disease Genes
Direct Interactants of Disease Genes
Mining human interactome
HPRDBioGrid
Which of these interactants are potential new candidates?
Indirect Interactants of Disease Genes
7
66
778
Prioritize candidate genes in the interacting partners of the disease-related genes•Training sets: disease related genes •Test sets: interacting partners of the training genes
Example: Breast cancer
OMIM genes (level 0)
Directly interacting genes (level 1)
Indirectly interacting genes (level2)
15 342 2469!
15 342 2469
PubMed
Medical Informatics
Patient Records
Patient Records
Disease Database
Disease Database→Name→Synonyms→Related/Similar Diseases→Subtypes→Etiology →Predisposing Causes→Pathogenesis→Molecular Basis→Population Genetics→Clinical findings→System(s) involved→Lesions →Diagnosis→Prognosis→Treatment→Clinical Trials……
Clinical Trials
Clinical Trials
Bioinformatics
Genome
Transcriptome
Proteome
Interactome
Metabolome
Physiome
Regulome Variome
Pathome
Ph
arm
acog
enom
e
Disease
World
OMIM
►Personalized Medicine►Decision Support System►Outcome Predictor►Course Predictor►Diagnostic Test Selector►Clinical Trials Design►Hypothesis Generator…..
Computer
Engineers
the Ultimate Goal…….