Presentation on theme: "Clinical-Genomics HL7 SIG"— Presentation transcript:
1 Clinical-Genomics HL7 SIG The Tissue Typing Use CaseAmnon Shabo1, Shosh Israel2, Guy Karlebach11IBM Research Lab in Haifa, 2Hadassah University HospitalPresented by Amnon ShaboSHAMAN = Secured Health and Medical Access NetworkIMR = Integrated Medical Records MiddlewareIn collaboration with the Hadassah University Hospital in JerusalemHaifa LabsIntegration of multiple sources of data; transformation to standards; full-text indexationWatson/YorktownLabsProcessing of personal genomic and proteomic data
2 Types of Genomic Data DNA Sequences Personal SNPs (Single Nucleotide Polymorphism)Programmatic / manual annotation (e.g., SNPs combination x could possibly lead to mutation y)Gene expression levelsProteomic (proteins translated w/SNPs)
3 The Case for Clinical-Genomics Clinical-Genomics: the use of information obtained from DNA sequencing, patterns of gene expression & resulted proteins for healthcare purposesPersonalized MedicineDetect sensitivities/allergies beforehandDrug Selection by cliniciansPharmacogenomicsImprove drug development based on clinical-genomics correlationsPersonal customization of drugsPreventive Care
4 Gene Expression in Cancer Differences between normal tissue vs. premalignant lesion vs. neoplastic tissuemarkers of diagnostic valuetargets for drug researchevolution of cancerDifferences between responders vs. non-responders for a standard therapyDevelopment of drug-resistanceCorrelation of gene expression patterns with presentation or evolution:long vs. short survivorsmetastatic vs. non-metastaticclinical or pathological grades
5 Differential DisplayDifference between banding patterns of cDNA from tumor tissue and normal tissue on polyacrylamide gel can point to a protein that could potentially be the target of a therapeutic antibody.DNA microarrays are also employed to examine the genetic expression of thousands of potential antigens and determine which are present in abnormal (tumor) tissue but not in normal tissue.
6 Using DatabasesVast databases of genetic information contribute to genomic researchSearch for potential antigens can be as easy as an online searchHLA Database example: (part of the IMGT - international immunogentics project)
7 Clinical-Genomics Interrelations Bi-directional relationships:Genomics ClinicalPersonal SNPs could be interpreted as mutations and thus indicate possible diseases/sensitivitiesClinical GenomicsPatient & family history leads to genetic testing orderCrosschecking of genomics results
8 SNPs InterpretationSNPs as known mutations (might imply the develop. of diseases)Unknown SNPs:in significant segments of the gene (possibly imply individual differences)in gene segments that translate to inactive parts of the proteins (thought to be insignificant)SNPs as normal polymorphisms
9 CG Uses: From Clinical to Forensic These pictures describes paternity casework autoRADS - the left picture shows a case of paternity exclusion and the right one a case of paternity inclusion.Paternity TestingTaken from the site of Genelex, a company which offers, among other genomic services, paternity testing (see
10 Variety of Methods STR (short tandem repeats ) STR’s are short sequences that are easy to detect and its specific pattern of repetitions could identify a gene without needing to sequence the entire gene.
11 HL7 Specs for Clinical-Genomics Create a DIM for Clinical-GenomicsDerive R-MIMs and message typesClinical-Genomic Documents (CDA L3!)Review / Utilize the following emerging bio-informatics standardsBSML (Bioinformatic Sequence Markup Language)MAGE-ML (Microarray and GeneExpression Markup Language)Problem: These standards are not necessarily patient-based.
15 Current Experimentations at IBM Research A clinical point of viewBone-marrow transplantation center in IsraelDonor-recipient matching: tissue typingReporting to international BMT registryA research point of viewResearch center in CanadaFocusing on heart&lung diseasesTrying to find clinical-genomic interrelationsUsing clinical data from patient records compared with healthy peopleUsing genomic data, mainly gene expression levels and proteins
16 Collaboration with Hadassah Information exchangeReport to international registries (IBMTR)StandardizationTransform to HL7-CDA documents (L.13)IndexingIndex all data including semi-structured dataAnnotationIntegrating the personal genomic dataVisualizationVisualizing the integrated BMT documents…agctgaa…SNPs
17 The BMT Procedure Pre-BMT BMT Post-BMT Matching a donor or autologous transplantConditioningIrradiationChemotherapyGVHD (Graft vs. Host Disease) ProphylaxisBMTSubstance donatedBone-marrowPeripheral blood stem cellsCord blood stem cellsDonor lymphocytes-TransplantPost-BMTControl of GVHD and other complicationsHematopoietic ReconstitutionEngraftment and Chimerism
18 Mini-allografts (mini-transplantations) New Trends in BMTMini-allografts (mini-transplantations)Immunosuppression instead of total conditioning (destroying the entire immune system)Infusing donor lymphocytes to attack tumors, cancerous cells, autoimmune artifacts and infectious pathogensStopping the donor lymphocytes once they’re done with the patient disease source, so that they won’t attack the patient normal cells using ‘suicide genes’Striking a balance between to 2 immune systems
19 The HLA-Typing Use Case HLA = Human Leucocytes Antigens; determine the personal fingerprint distinguishing between self and non-selfHLA-Typing methods move from serology (antibodies) to molecular (DNA) and recently to DNA sequencing yielding higher levels of typing resolutionCommon Triggers: donor-recipient matching, familial relationships, disease association
20 Donor Matching HLA (Human Leukocytes Antigens) HLA Typing DNA typing About 6 important loci, each can have dozens of different antigens (alleles)Haplotype – common set of antigensRelatives versus unrelated donationDonor banksSearch enginesLack of donors to minorities
22 Differences in Antigens Allelic polymorphism is concentrated in the peptide (antigen) binding site:Class IIVariables exons: 2Class I:Variables exons: 2,3,4
23 The HLA-Typing Triggers Donor-Recipient MatchingBone-Marrow transplantFull match (identical twin)Avoid GVHD and Promote GVM Precise and personal match rather than full matchOrgan transplant (cross-match: antibodies)Living donor: also HLA typing before transplantSelect the best treatment for the individual patient-donor matchingHLA-typing is done for post-transplant Info.Forensic ScenariosPaternity disputesCrime suspects (HLA is one component of known genetic markers)
24 Personal Rather than Full Match Personal match could be beneficial to to new trends in BMT:HLA - A & B versus C:When there is a match in HLA A & B:Mismatch in HLA-C might promote GVL (Graft vs. Leukemia)Mini-transplants:Avoid full-match (even when identical twin is available)
25 Data of Interest Class I allele sequences (all cells): HLA-A HLA-B HLA-CClass II allele sequences (certain cells from the immune system):HLA-DR (most important)HLA-DQ (the contribution is not proven but can verify the DR match since there there is strong linkage)HLA-DP (usually is not being typed)might sequence only the polymorphic segments (e.g., exon 2 in class II and exon 2-4 in class I), each exon is about a 300 nucleotides, because SNPs in other segments are not important to the matching
26 New Naming Convention DOB*01010101 Letter designates the membrane locusFull allele name: eight digitsFirst 2 digits defining the allele family and where possible corresponding to the serological familyThird and fourth digits describing coding variationFifth and sixth digits describing synonymous variationSeventh and eighth digits describing variation in intronsDOB*
27 Sequencing Data Example: Generic Meta Data:Local Names: DRB1*110101IMGT/HLA No: HLA00756Class: IIAssigned: 01-AUG-1989Last Aligned: 17-OCT-2002Component Entries: AF AJ297587Cell Sequence Derived From: 34A2, FPAFKnown Ethnic Origin of Cells: CaucasoidLength: bps
28 Sequencing Data Example: DRB1*110101IMGT-HLA SEQUENCE DATABASE.htmSNPs
29 Sequencing Data Example: SNP-Resulted Protein SequenceIMGT-HLA SEQUENCE DATABASE.htm
30 Sequencing Data Example: DRB1*110401IMGT-HLA SEQUENCE DATABASE2.htmSNP
31 Sequencing Data Example: SNP-Resulted Protein SequenceIMGT-HLA SEQUENCE DATABASE2.htm
32 Testing Kit Output Example - Sample ID - Kit Name- Name - Kit Lot Number- Ethnic Group - Kit Expires- Donor/Patient - DNA Extraction- Purpose of Test - DNA Quality- Test Date - DNA Concentration- Test By - Review Date- Comments - Reviewed BySerology Results: HLA A: B: C: DR: DQ: Positive Lanes:Kit-specific data
33 Tissue Typing Report Recipient Subject Specific Alleles Record Number Molecular SampleDateDiseasePatient ResultSpecific AllelesPossible combinationsSiblingsUnrelated Donors
34 Search for Unrelated Donor Banks of potential donors (volunteers)Each donor was tested only for HLA Class IWhen a patient needs a donor:The transplant facility searches the donor banks to find a donor (direct access to the donor banks databases)The search is based on Class I matchingIf appropriate donors are found – then the searching transplant facility initiates a request to the respective donor banks, asking for Class II typingEach approached donor bank is moving the request to the tissue typing lab where the DNA samples resideClass II matching results are returned to the searching facility and if the donor with the best match in both class I & II is approached
35 Search for Unrelated Donor Donor BanksTransplant Center (TC) searches for donorsPatient Class I HLADonor BanksClass I Matching donorsTC chooses potential donorsDonor BankRequest for HLA class II typingTC chooses best donorClass II Matching donorsTissue Typing LabClass II Typing
36 Genomic Data in a Clinical Docs A DNA Testing Device – raw DNA sequencesReports from service units, e.g., tissue typing, should answer questions such as patient-donor matching, fatherhood, etc.Embedding annotated results received from a DNA lab in a CDA documentLinking genomic annotations and clinical data (external links?)
37 Matching Option Notations Different notations for coarse-grain results:possibilities from the A24 antigen family could be represented differently by different kits on the same patient DNA tested:A* /08-11N/13-15/17/18/20-23/25-36NA* /08-11N/13-15/17/18/20-23/25-31Pair combinations (inherited alleles):DRB1*0402 AND DRB1*0408 or DRB1*0404/44 AND DRB1*0414Kit A:Exact combinationKit B:twopossiblecombinationsor
38 Report Example – Unrelated Donors The PatientUnrelated Donor 2Unrelated Donor 1Unrelated Donor 3
39 Class I vs. Class II Antigens A 4-digit resolution level is common in class II antigens as they have been discovered more latelyIt’s desired that class I antigens will report in 4 –digits as well as they are more crucial to BMT success4-digits reporting requires molecular and sequencing procedures4-digits reporting still not common in class I
40 Clinical-Genomic Data in CDA? What should go into a clinical document (extent of detail)?Programmatic and manual annotation at different levels?The users of such integrated documents: clinicians? genomicists? patients? Medico-ethical issues!HL7-Association semantics that represents the interrelations of clinical-genomics
41 First Attempts using CDA… GMSGenetic Messaging SystemFrom the computational biology center in IBM WatsonExample: integrating the genomic annotation and analysis of the personal DNA sequences, into the clinical document (CDA format)<levelone><clinical_document_header><!--header structures per CDA--></clinical_document_header><body><!--clinical content per CDA--><!--GMS merges genomic data here--><gms:dna sequence="2" base="802" locus="1"><gms:annotation>possible somatic mutation cell line #4 end-11th</gms:annotation>AGGAATCAGAAAGGACACTCTGGACTTCAGCCAACAGGATACCTGAGCTGA...<gms:automated_annotation></body></levelone>CDA L1
42 And the Work Just Begins… Use Cases in Detail & TaxonomyHigh-Level CG Model and HL7-DIMMessagesDocumentsPrototyping info. Exchange using specsThanks You!
Your consent to our cookies if you continue to use this website.