Transcript
국민의료진단시스템개발의미래:BioBank (인체자원은행) Big+Data+와 AI+의융합
K.+Hun+Mok++(睦憲),+Ph.D.+Trinity+College+DublinTrinity)Biomedical)Sciences)Institute)(TBSI)School)of)Biochemistry)and)ImmunologyProtein)Folding)and)Biomolecular)NMR)Spectroscopy)Lab)/)TBSI)NMR)FacilityDublin)2,)Ireland
17th September+2021+(Fri)
<제 9차> 바이오헬스
2021년글로벌신산업J신기술세미나Online)Symposium,글로벌기술협력지원단 (KGTAG)한국산업기술진흥원 KIAT
AcknowledgementsLouise'M.'Sullivan''''''''Níal P.'Harte''''''''''''''Yongjing Xie
Pancham S.'Kandiyal Anna'Hastings''''''''''Ji'Yoon'Kim''''''''Daniel'L.'FortunatiSoyoung'Min''''''Yeon'Joong'Yong''''''''''Ki Hyung Kim''''''''''''''Sohyun'Kim
Catharina'Svanborg (Lund'University,'Sweden)'''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''André'Brodkorb (Teagasc'Food'Research'Centre,'Moorepark)Michael'J'Rowan (Trinity'College'Dublin)John'J'Boland'''''' (Trinity'College'Dublin)Kyou Hoon Han''''''''''''''''''(KRIBB,'Korea'Research'Inst'of'Biosci and'Biotech)Eun Kyu Lee'''''''''''' (Hanyang'University,'Ansan,'Korea)
Funding:'''FIRM'(DAFM),'Enterprise'Ireland'(Rep'of'Ireland)''/Swedish'Research'Council''(Sweden)'''/''''''BBSRC'(UK)'
Lee/Sherlock///////////Brendan/Martin//////////////Sinha/Behsanger
Table&1.&Basic&characteristics&of&KarMeN&study&participants.
Rist%MJ,%Roth%A,%Frommherz%L,%Weinert%CH,%Krüger%R,%et%al.%(2017)%Metabolite%patterns%predicting%sex%and%age%in%participants%of%the%Karlsruhe%Metabolomics%and%Nutrition%(KarMeN)%study.%PLOS%ONE%12(8):%e0183228.%https://doi.org/10.1371/journal.pone.0183228https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0183228 인체
자원은행
(Bioban
k)*의
축소형예
Fig$1.$Metabolite$patterns$for$the$prediction$of$sex.
Rist%MJ,%Roth%A,%Frommherz%L,%Weinert%CH,%Krüger%R,%et%al.%(2017)%Metabolite%patterns%predicting%sex%and%age%in%participants%of%the%Karlsruhe%Metabolomics%and%Nutrition%(KarMeN)%study.%PLOS%ONE%12(8):%e0183228.%https://doi.org/10.1371/journal.pone.0183228https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0183228
Plasma Urine
Male$ Female Male$ Female
Table&2.&Prediction&accuracy&of&sex&of&the&KarMeN&study&participants&based&on&metabolite&profiles&in&plasma&and&urine&using&different&algorithms.
Rist%MJ,%Roth%A,%Frommherz%L,%Weinert%CH,%Krüger%R,%et%al.%(2017)%Metabolite%patterns%predicting%sex%and%age%in%participants%of%the%Karlsruhe%Metabolomics%and%Nutrition%(KarMeN)%study.%PLOS%ONE%12(8):%e0183228.%https://doi.org/10.1371/journal.pone.0183228https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0183228
Fig$2.$Metabolite$patterns$for$the$prediction$of$age$in$men.
Rist%MJ,%Roth%A,%Frommherz%L,%Weinert%CH,%Krüger%R,%et%al.%(2017)%Metabolite%patterns%predicting%sex%and%age%in%participants%of%the%Karlsruhe%Metabolomics%and%Nutrition%(KarMeN)%study.%PLOS%ONE%12(8):%e0183228.%https://doi.org/10.1371/journal.pone.0183228https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0183228
Plasma Urine
Younger$ Older Younger$ Older
Table&3.&Prediction&of&chronological&age&of&the&KarMeN&study&participants&based&on&metabolite&profiles&in&plasma&and&urine&using&different&algorithms.
Rist%MJ,%Roth%A,%Frommherz%L,%Weinert%CH,%Krüger%R,%et%al.%(2017)%Metabolite%patterns%predicting%sex%and%age%in%participants%of%the%Karlsruhe%Metabolomics%and%Nutrition%(KarMeN)%study.%PLOS%ONE%12(8):%e0183228.%https://doi.org/10.1371/journal.pone.0183228https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0183228
S2 Fig.: Concentrations of selected metabolites contained in metabolite patterns
important for prediction of age in male study participants versus age. Plots are
shown for (A) plasma and (B) urine metabolites of male study participants with mean rank
1 (left panel) and 25 (right panel). PO4, phosphate; U2.50, unknown NMR analyte at 2.5
ppm; 4-HMA, 4-hydroxymandelic acid; a.u., arbitrary units.
Urine
Plasma
대사체학 Metabolomics
시스템생물학Systems'Biology
Metabolomics
Metabonomics
Integration*of*genomic,*transcriptomic,*proteomic,*etc*data*to*understand*function*through*different*levels*of*biomolecular*
organization.
Measurement*of*metabolite*fluxes*and/or*secretionsin*cells*and*tissues.
Measurement*of*multivariate*metabolic*responses*due*to*pathophysiological*stimuli*or*genetic*modification.
TRACT'NMR'Metabolomics'Training KH'Mok
U P SmSa Se WBBS C5"Hydroxyindoleacetic0acid Intestinal0Carcinoid0syndrome0 LCMSAcylcarnitines0 Fatty0acid0oxidation0disorders,0several0organic0acidurias0and0new0born0screening0 ESI"MSAcylglycines0 Inborn0errors0of0metabolism0 Capillary0GCMSAllo"isoleucine New0born0screening:0branched0chain0amino0acids0elevations0 LCMSAmino0acid0(Panel) Inborn0errors0of0metabolism:0ovaluation0of0endocrine0and0neurological0disorders,0liver,0muscle0&0neoplastic0diseases0 LCMSAminolevulinic0acid Various0acute0hepatic0porphyrias0 LCMSBile0acid0 Liver0dysfunction Enzymatic0&LCMSCarnitines0 Organic0acidemias,0fatty0acid0oxidation0disorders0and0primary0carnitine0deficiency0 MScarotene"0beta Fat0Malabsorption0 HPLCCeramides Myocardial0infarction,0cardiovascular0disease0and0mortality0within050years0 LCMSCholesterol0 Evaluation0of0cardiovascular0risk0 Enzymatic0&LCMSCitric0acid Metabolic0disease0 Enzymatic0SpectrophotometryCortisol0 Cushing0syndrome0&0adrenal0insufficiency0 LCMS0&Immunoenzymatic0AssaysCeatine0 Renal0function0 Enzymatic0d"lactate0 d"lactate0acidosis0 EnzymaticEthylmalonic0acid New0born0screening0 LCMSFatty0acid0profiles0 Identifying0deficiency0of0essential0and0other0nutritionally0beneficial0fatty0acids0 Capillary0GCMSFructosamine0 Glyceamic0control0 ColourmetricFructose Azoospermia0 Qualitative0Test0Galactitol0 Galactosemia0 GCMSGlucose Diabetes0&0carbohydrate0metanolism0disorders0 Photometric0Glutaric0acid0 New0born0screening0 LCMSHDL0cholesterol0 Cardiovascular0risk0 Colourmetric0&0EnzymaticHippuric0acid Liver0function0 LCMSHistamine0 Allergies0and0mast0cell0disorders0 Immunoenzymatic0Assays0Homocysteine Inherited0disorders0of0methionine0metabolism0 ESI"MSHomovanillic0acid0 Screening0children0for0catecholamine"0secretig0tumours0 LCMSHydroxyglutaric0acid0 New0born0screenings LCMSInsulin Insulinoma0 Electrochemiluminescence0Immunoassyas0Lactate0 Lactic0acidosis0&0differentiating0between0bacterial0and0viral0meningitis0 Photometric0LDL0Cholesterol0 Cardiovascular0risk0 Colourmetric0&0EnzymaticMethylmalonic0acid0 Methylmalonic0acidemia0 LCMSMethylsuccinic0acid New0born0screenings0 LCMSOrganic0acid0screen0 Inborn0erros0of0metabolsim0 GCMSphenylalanine0and0tyrosine0 Hyperphenylalaninemia MSPhospholipids0 Lecithin"cholesterol0acyltransferase0deficiency0 ColourmetricPipecolic0acid Peroxisomal0biogenesis GCMSPurines0and0pyramidines0(panel) Disorders0of0purine0and0pyrimidine0metabolism0 LCMSPyridoxal05"phosphate Progressive0nerve0compression0disorders0 LCMSPyruvate0 Disorders0of0mitochondrial0metabolism0 Spectroscopy0Riboflavin0vitamin0B20 Ariboflavinosis0 LCMSThiamine0 Behavoural0change,0delerium,0dietry0concerns0 LCMSTriglycerides0 Elevated0cholesterol0values0 EnzymaticUrea0 Renal0failure0 UVUric0acid0 Acute0uric0acid0nephropathy0from0other0causes0of0acute0renal0failure0 Enzymatic0&Photometric0
Biological/Matrix/
Analytical/Test/Clinical/Relevance/Biomarker/
Clinically(useful(biomarkers.(U:#urine,#P:#plasma,#Sm:#saliva,#WB:#whole#blood,#BS:##dried#blood#spot,C:#CSF#(cerebrospinal#fluid).
Originally#sourced#from#the#Mayo#Clinic,#US.[Ref:#D.#K.#Trivedi,#K.#A.#Hollywood,#and#R.#Goodacre,#New$Horiz Transl Med,$vol.#3:#294Q305,#2017. ]
유전체학 | 전사체학 | 단백질체학 | 대사체학Genomics**|**Transcriptomics**|****Proteomics***|**Metabolomics
Biomarker바이오마커도출
Personalized/Medicine맞춤형의학
Metabolomics, Relatively,Large,Data,Sets,(1)
305,214,da
ta,points
Metabolomics Relatively/Large/Data/Sets/(2)
32,700/rows/x/143/subjects
MetabolomicsVisualizing*metabolic*space*and*influence*vectors�Principal*Components*Analysis*(PCA)�
TRACT%NMR%Metabolomics%Training KH%Mok
다변량분석Multivariate/Analysis
유전체학 | 전사체학 | 단백질체학 | 대사체학Genomics**|**Transcriptomics |****Proteomics***|**Metabolomics
Mok$KH$group$expertise:$$$Instrumentation
The$NMR$Facility$at$Trinity
High%resolution.NMR.capacity.realises:
% Novel&drug&development&(“SAR%by%NMR”)% The&validation&of&molecular&identity(biosimilars /&protein&aggregation)
% Metabolomics of&cells,&serum,&urine&–Large?scale&biobank profiling
% Atomic?level&3D&biomolecular&structure&&&&&% Structure&elucidation&of&nano?scale&/inorganic&materials
! Currently*the*highest*magnetic*field*in*all*of*Ireland*and*NI.
! Equipped*with*1H/15N/13C*cold*(cryo)*probe,*biomolecular*solid*state*MAS*probes,*triple*axial*pulsed!field*gradient*probes,*etc.
! With*the*cold*probe,*capabilities*of*detecting$metabolites$and$in#vivo#sample$concentrations$of$sub@μmolar range.
What%is%NMR?% High%resolution, atomic%level methodology forthe determination of chemical and biochemicalstructures of molecules.% Proteins, nucleic acids, sugars, lipids, drugs
The%principleof%NMR%isidentical%to:
Mok$KH$group$expertise:$$$Instrumentation
The$NMR$Facility$at$TCD$$$(800$MHz)
High%resolution.NMR.capacity.realises:
% Novel&drug&development&(“SAR%by%NMR”)% The&validation&of&molecular&identity(biosimilars /&protein&aggregation)
% Metabolomics of&cells,&serum,&urine&–Large?scale&biobank profiling
% Atomic?level&3D&biomolecular&structure&&&&&% Structure&elucidation&of&nano?scale&/inorganic&materials
! Currently*the*highest*magnetic*field*in*all*of*Ireland*and*NI.
! Equipped*with*1H/15N/13C*cold*(cryo)*probe,*biomolecular*solid*state*MAS*probes,*triple*axial*pulsed!field*gradient*probes,*etc.
! With*the*cold*probe,*capabilities*of*detecting$metabolites$and$in#vivo#sample$concentrations$of$subGμmolar range.
NMR$Metabolomics$: Projects)from)the)Mok)KH)lab.
" High$quality$biobanks: Longitudinal-samples-/-Historical-documentation
Case%Study:%%Renal%Vasculitis%in%Humans(Inflammation+of+the+kidney)
Case%Study:%%Renal%Vasculitis%in%Humans(Inflammation+of+the+kidney)
2 Succesful+identification+of+biomarkers+that+can+be+used+for+diagnosis.
2 Myoinsotol+– Citrate+ratio+in+patient+urine.
Al+Ani++B,+et+al,+Scientific(Reports,+2016
ExperimentsDatabases
PRE-
PROC
ESSI
NGIN
TEGR
ATIO
NIN
TERP
RETA
TION
VISUALISATION
Normalisation Dimensionality reduction
Bayesian Network Fusion Similarity
Assumptions on prior distributions
Posterior probability distribution
Individual networks
Joint network
Alignment of local samples
Fusion of data in uniform
representation
Construction of similarity matrix
Integration of each matrix into a
uniform matrix
Through Bayes theorem
Through e.g. correlation
analysis
e.g. PCA
Omic Data
SUBTYPES BIOMARKERS
INSIGHTS
5
3
4
2
1
General'integration'pipeline'of'the'multiomics in'which(1) Gathering'of'data'through'databases'or'experiments;'(2) Pre=integration'step'to'ensure'correct'integration;'(3) Integration'of'data'through'a'selected'statistical'method;'(4) Visual'representation'of'data'processed'by'the'integrative'tools;(5) Interpretation'of'the'integrated'and'visualised data'to'identify'subtype'and'
biomarkers'as'well'as'new'insights'into'the'studied'disease
Metabolomics, Relatively,Large,Data,Sets,(1)
Originally,**301*Rows*x*507*Columns
Of*these,*in*our*analysis,*use*only*NMR*data
=*301*Rows*x*176*Columns*
Table&2.&Prediction&accuracy&of&sex&of&the&KarMeN&study&participants&based&on&metabolite&profiles&in&plasma&and&urine&using&different&algorithms.
Rist%MJ,%Roth%A,%Frommherz%L,%Weinert%CH,%Krüger%R,%et%al.%(2017)%Metabolite%patterns%predicting%sex%and%age%in%participants%of%the%Karlsruhe%Metabolomics%and%Nutrition%(KarMeN)%study.%PLOS%ONE%12(8):%e0183228.%https://doi.org/10.1371/journal.pone.0183228https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0183228
Increases&to&97%
Table&3.&Prediction&of&chronological&age&of&the&KarMeN&study&participants&based&on&metabolite&profiles&in&plasma&and&urine&using&different&algorithms.
Rist%MJ,%Roth%A,%Frommherz%L,%Weinert%CH,%Krüger%R,%et%al.%(2017)%Metabolite%patterns%predicting%sex%and%age%in%participants%of%the%Karlsruhe%Metabolomics%and%Nutrition%(KarMeN)%study.%PLOS%ONE%12(8):%e0183228.%https://doi.org/10.1371/journal.pone.0183228https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0183228
S2 Fig.: Concentrations of selected metabolites contained in metabolite patterns
important for prediction of age in male study participants versus age. Plots are
shown for (A) plasma and (B) urine metabolites of male study participants with mean rank
1 (left panel) and 25 (right panel). PO4, phosphate; U2.50, unknown NMR analyte at 2.5
ppm; 4-HMA, 4-hydroxymandelic acid; a.u., arbitrary units.
Urine
Plasma
Improves&to&97&%
Metabolomics Relatively/Large/Data/Sets/(2)
32,700/rows/x/143/subjects
Test/Set/prediction/accuracy/for/lung/cancer:///95%
Perspective*+ Overview! What&biomedical&R&D&has&accomplished&!
Genomics(Personalized&Genome&Screening)
Common&Objectives&of&each&Large&Initiative:! Profiling&of&representative&patient&samples! Compare/Contrast&the&differences! Multivariate&Stat&Analyses! Biomarker&identification&
Proteomics(Not&all&of&the&transcriptome is&translated.)
Transcriptomics(Not&all&of&the&genome&is&expressed.)
Lipidomics /*Gly(c)omics(Not&all&of&the&proteome&is&&glycosylated.)
! Drug*Discoveryand*Development
Perspective*+ Overview! What&biomedical&R&D&has&accomplished&!
Genomics(Personalized&Genome&Screening)
Proteomics(Not&all&of&the&transcriptome is&translated.)
Transcriptomics(Not&all&of&the&genome&is&expressed.)
Lipidomics /*Gly(c)omics(Not&all&of&the&proteome&is&&glycosylated.)
Metabolomics(Manifestation&of&all&of&the&above&+&The&Environment)
Multiomicrepositories-
Emphasis:)Genomics
Emphasis:)Other)Omics
Our$Proposal$–
Marriage'of:
Big'Data'IT'Acquisition'/'Analysis'/'Archiving+
Detailed'and'individualizedbiomedical'data'(='patient'and/or'biobanks)
='''True'interdisciplinary,holistic'vision'&'toolsfor'the'treatmentand'prevention'of''''human'diseases.
전체그림을항상염두에두며,
한 "Omics,(한 –Omics(씩풀어간다.
Trinity'College'Dublin! The%University%of%Dublin%!
! Founded%1592%! Highest%ranked%university%in%Ireland%! Strengths
! Humanities%and%Social%Sciences%%%(Traditional)! Nanosciences! Neurosciences! Biochemistry%&%Immunology
Trinity%Biomedical%Sciences%Institute(TBSI)
Kells사본The'Book'of'Kells
The$Book$of$KellsHoused'in'the'
, Trinity'College'Dublin'Library',
Thank&youfor&yourattention.
Trinity'College,'the'University'of'Dublin
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