Implementation Guide for CDA Release 2 Genetic Testing Report (GTR)

Transcription

1 Implementation Guide for CDA Release 2 Genetic Testing Report (GTR) (Universal Realm) Draft Standard For Trial Use September 2012 CDAR2_IG_GENTESTRPT_R1 (Developer Documentation)

2 Introduction 2

3 TOC 3 Contents Authors... 5 Acknowledgments... 7 Revision History...9 List of Figures List of Tables Chapter 1: INTRODUCTION Purpose Approach Scope Audience...17 Organization of This Guide...17 Templates Vocabulary and Value Sets Use of Templates...18 Originator Responsibilities...18 Recipient Responsibilities Note on Draft Standards...18 Conventions Used in This Guide...18 Conformance Requirements...18 Keywords...19 XML Examples Contents of the Ballot Package Chapter 2: DOCUMENT TEMPLATES...21 Genetic Testing Report...22 Chapter 3: SECTION TEMPLATES...39 Background Section Findings Section...41 Indications Section Interpretation Section Methodology Section Overall Interpretation Section Performers Section Recommendations Section References Section Specimen Section Summary Of Tests Performed Section...52 Summary Section Test Details Section...58 Test Information Section...65 Test Performed Section... 68

4 TOC 4 Chapter 4: CLINICAL STATEMENT TEMPLATES Clinical Genomic Statement...73 Clinical Genomic Statement Cytogenetics...75 Clinical Genomic Statement Gene Expression Clinical Genomic Statement Genetic Variation Clinical Genomic Statement Overall Interpretation...83 Cytogenetics Associated Observation Cells Analyzed Count...85 Cytogenetics Associated Observation Cells Count...86 Cytogenetics Associated Observation Cells Karyotyped Count Cytogenetics Associated Observation Colonies Count...87 Cytogenetics Associated Observation ISCN Band Level Genetic Variation Associated Observation Amino Acid Change Genetic Variation Associated Observation DNA Change Genetic Variation Associated Observation DNA Region Name...91 Genetic Variation Associated Observation Zygosity Genomic Associated Observation Genomic Observation Reference...93 Genomic Observations Organizer Genomic Source Class...94 Indication Observation Interpretive Phenotype Interpretive Phenotype Cytogenetics...96 Interpretive Phenotype Gene Expression Interpretive Phenotype Genetic Variation...97 Interpretive Phenotype Pharmacogenomic...98 Interpretive Phenotype Pharmacogenomic Drug Efficacy...99 Interpretive Phenotype Pharmacogenomic Drug Metabolism Overall Interpretive Phenotype Chromosome Analysis Overall Interpretive Phenotype Genetic Disease Overall Interpretive Phenotype Genetic Disease Carrier Overall Interpretive Phenotype Pharmacogenomic Drug Efficacy Overall Interpretive Phenotype Pharmacogenomic Drug Metabolism Test Performed Observation Chapter 5: OTHER CLASSES Chapter 6: VALUE SETS Allelic State Amino acid change type Chromosome analysis overall interpretation DNA sequence variation change type Drug efficacy analysis overall interpretation Drug Efficacy Sequence Variation Interpretation Drug metabolism analysis overall interpretation Drug metabolism sequence variation interpretation Genetic disease analysis overall carrier interpretation Genetic disease analysis overall interpretation Genetic disease sequence variation interpretation Genomic source class ISCN band level REFERENCES

5 Authors Primary Editor Co-Editor CG and SDWG Members Amnon Shabo, Ph.D. IBM Research Lab in Haifa Mollie Ullman-Cullere MS, MSE Department of Clinical Research Informatics Dana-Farber Cancer Institute If you're interested in contributing to the development of the GTR IG, please contact Amnon Shabo. Last Published: 10/05/2010 HL7 Version 3 Standard, 2005 Health Level Seven, Inc. All Rights Reserved. HL7 and Health Level Seven are registered trademarks of Health Level Seven, Inc. Reg. U.S. Pat & TM Off

6 Authors 6 Genetic Testing Report (GTR) Page 6

7 Acknowledgments We acknowledge the foundational work on HL7 Version 3 and the Reference Information Model (RIM), the HL7 domain committees, especially the work done by the Structured Documents Work Group on Clinical Document Architecture (CDA) itself. We acknowledge the efforts of the HL7 Clinical Genomics Work Group which has been developing v3 specifications for the past seven years as well as v2 implementation guide for genetic testing results message. Note that the LOINC codes developed within the v2 effort are utilized in this GTR IG. We acknowledge the efforts the MDHT tool developers who work closely and tirelessly with us to accommodate the requirements of the GTR. This material contains content from LOINC ( The LOINC table, LOINC codes, and LOINC panels and forms file are copyright , Regenstrief Institute, Inc. and the Logical Observation Identifiers Names and Codes (LOINC) Committee and available at no cost under the license at

8 Acknowledgments 8 Genetic Testing Report (GTR) Page 8

9 Revision History Rev Date By Whom Changes New 8 January 2009 Amnon Shabo New Draft 1 3 August 2010 Amnon Shabo CGWG review DSTU R1_O1 10 August 2010 Amnon Shabo CGWG review Draft For Comment R1_O2 March 2011 Amnon Shabo CGWG review Draft For Comment R1_O3 September 2011 Amnon Shabo CGWG review (note that reconciliation of negative comments has not been completed) Draft For Comment May 2012 Amnon Shabo Informal Review Draft Standard For Trial Use September 2012 Amnon Shabo Ballot

10 Revision History 10 Genetic Testing Report (GTR) Page 10

11 TOC 11 List of Figures Figure 1: Template name and "conforms to" appearance...18 Figure 2: Template-based conformance statements example...19 Figure 3: Conformance statements example (taken from the CCD IG) Figure 4: ClinicalDocument example...19 Figure 5: Genetic Testing Report example...23 Figure 6: Background Section example...40 Figure 7: Findings Section example Figure 8: Indications Section example Figure 9: Interpretation Section example Figure 10: Methodology Section example...44 Figure 11: Overall Interpretation Section example Figure 12: Performers Section example Figure 13: Recommendations Section example Figure 14: References Section example Figure 15: Specimen Section example Figure 16: Summary Section example...54 Figure 17: Test Details Section example Figure 18: Test Information Section example Figure 19: Clinical Genomic Statement example...74 Figure 20: Clinical Genomic Statement Cytogenetics example Figure 21: Clinical Genomic Statement Gene Expression example...79 Figure 22: Clinical Genomic Statement Genetic Variation example Figure 23: Clinical Genomic Statement Overall Interpretation example Figure 24: Cytogenetics Associated Observation Cells Analyzed Count example...86 Figure 25: Cytogenetics Associated Observation Cells Count example... 86

12 TOC 12 Figure 26: Cytogenetics Associated Observation Cells Karyotyped Count example Figure 27: Cytogenetics Associated Observation Colonies Count example Figure 28: Cytogenetics Associated Observation ISCN Band Level example...89 Figure 29: Genetic Variation Associated Observation Amino Acid Change example...90 Figure 30: Genetic Variation Associated Observation DNA Change example...91 Figure 31: Genetic Variation Associated Observation DNA Region Name example...91 Figure 32: Genetic Variation Associated Observation Zygosity example Figure 33: Genomic Associated Observation example Figure 34: Genomic Observation Reference example...93 Figure 35: Genomic Observations Organizer example Figure 36: Genomic Source Class example...95 Figure 37: Indication Observation example Figure 38: Interpretive Phenotype example...96 Figure 39: Interpretive Phenotype Cytogenetics example...97 Figure 40: Interpretive Phenotype Gene Expression example Figure 41: Interpretive Phenotype Genetic Variation example Figure 42: Interpretive Phenotype Pharmacogenomic example...99 Figure 43: Interpretive Phenotype Pharmacogenomic Drug Efficacy example Figure 44: Interpretive Phenotype Pharmacogenomic Drug Metabolism example Figure 45: Overall Interpretive Phenotype Chromosome Analysis example Figure 46: Overall Interpretive Phenotype Genetic Disease example Figure 47: Overall Interpretive Phenotype Genetic Disease Carrier example Figure 48: Overall Interpretive Phenotype Pharmacogenomic Drug Efficacy example Figure 49: Overall Interpretive Phenotype Pharmacogenomic Drug Metabolism example Figure 50: Test Performed Observation example...106

13 TOC 13 List of Tables Table 1: Contents of the Ballot Package...20

14 TOC 14

15 Chapter 1 INTRODUCTION Topics: Purpose Approach Scope Audience Organization of This Guide Use of Templates Conventions Used in This Guide Contents of the Ballot Package The purpose of this Implementation Guide (IG) is to specify a standard for Genetic Testing Reports. In this project, the Clinical Genomics Work Group develops a CDA Implementation Guide (IG) for genetic testing reports, with the support of the Structured Documents Work Group. Note that this spec has passed DSTU ballot but is still being refined based on reconciliation of negative ballot comments. Early adopters are welcome but should be aware that final spec could be different than the current version. A few complete GTR samples are provided in the package containing this guide but only the hearing loss sample has been adjusted to the latest structure. XML snippets are automatically generated by the editing tool and placed as figures demonstrating the various templates of this guide. Nevertheless, these XML snippets are often merely skeletal and may not be accurate contentwise. Therefore, for best viewing of the XML snippets, it is recommended to first go through the complete samples provided in the ballot package.

16 INTRODUCTION 16 Purpose Genetic tests have recently become an important tool in clinical care that further personalizes the care processes based on the patient individual genetic makeup. Genetic testing methods are diverse and span from testing for known germline mutations in the context of single-gene disorders, to full sequencing of genes in tumor tissues looking for somatic variations in cancer cells. We also see the emerging use of gene expression testing in clinical care and it is expected to see a growing use of research techniques adjusted to healthcare. As a consequence of that diversity and the constantly growing number of techniques yielding new result formats less familiar to clinicians, we see existing report formats having emphasis on detailed but easy-to-understand interpretations of the testing results along with recommendations. These interpretations may originate from the laboratory or they may be created by a clinician specializing in genetic/genomic medicine. This work also supports, communication within the report itself, detailed information on the tests performed including references to the appropriate scientific studies and publications in a format that looks quite often like a short abstract in a scientific journal. Within the clinical environment, genetic test results typically flow from the genetic testing laboratory into the electronic health record (EHR). From the EHR these results may flow into another EHR or a personal health record (PHR). In some realms the first transmission of this data (from the laboratory into the EHR) is performed using the Laboratory message standard. Clinical Genomics has written an implementation guide which extends this standard for the support of clinical genetics (HL7 Version 2 Implementation Guide: Clinical Genomics; Fully LOINC-Qualified Genetic Variation Model, Release 1 (US Realm) ). In some realms, the second transmission of this data (EHR to EHR/PHR) is performed using the CCD message model (a constrained version of the CDA model). As such for the healthcare specific message, this implementation guide will minimally detail how certain data sets defined in the above mentioned implementation guide would be included using the CDA model as appropriate to the level of granularity of this human-readable report. Note: The producers of GTR documents include genetic laboratories as well as clinical geneticists or any clinician who needs to create a report summarizing genetic testing results (and is capable and authorized to do so). In addition, all roles in a research environment that needs to summarize genetic assays are included in the scope. Approach The following GTR IG design principles are based on requirements analysis through collecting requirements from various stake-holders of genetic testing reports. Convey findings and emphasize interpretations and recommendations (in the clinical environment, interpretations should be related to clinically relevant findings) Provide in-line information on tests performed Represent interpretation by utilizing patterns of genotype-phenotype associations in the HL7 v3 Clinical Genomics and implement them as harmonized clinical statement entry-level templates in this IG Represent a 'genetic study' by allowing different types of testing's to be included in the same GTR report, e.g., genetic variations, cytogenetics, gene expression etc.,all possibly contributing to the "overall interpretation" based on the interpretations of the discrete testings. Reference HL7 Clinical Genomics instances as the place holders of raw data (personal evidences) similarly to referencing images In particular, the GTR is organized as follows: The layout of the GTR starts with a summary section and ends with general information about the test performed; In between these two sections there are the specialized sections (represented by TestDetailsSection)describing specific genetic testing performed The rendered portion of the GTR (aka "narrative") is placed in the text attributes of sections and sub-sections The structured portion of the GTR is carried by the "ClinicalGenomicStatement" template. At its core, it has a genomic observation, optionally associated on the one side with indications for performing this observation and on the other side with interpretations of that observation Genetic Testing Report (GTR) Page 16

17 INTRODUCTION 17 A number of ClinicalGenomicStatement's can be placed in the TestDetailsSection which serves as a blueprint for specialized sections describing genetic variations, cytogenetics, gene expression, etc. Interpretations of a genomic observation are placed in sub-templates of the InterpretivePhenotypeObservation (an abstract class), for example, InterpretivePhenotypeObservationGeneticVariation The summary section has the following sub-sections: indications, summary of test performed, specimen, overall interpretation and recommendations. Regarding the tests performed section, it is similar to the TestPerformedSection, but can hold several tests (with concise descriptions) in contrast to the TestPerformedSection residing in each specific testing section and could have more detail about that specific test Sections that don't have a sub-template of "ClinicalGenomicStatement" or of "InterpretivePhenotypeObservation", merely carry narrative content A TestInformationSection can appear in each of the specific test sections if more detail is needed or if each test has its own description and there is no general description of all tests Notes: 1. The XML figures (snippets) are generated automatically the editing tool (MDHT); if they are empty or merely skeletal, please refer to the complete XML samples enclosed in the ballot package 2. Constraints on the value attribute have been described in free text similar to Object Constraining Language (OCL) statements. In later releases of this guide, all constraints will be represented in OCL and thus could be validated Scope The scope of this project is to define a Universal CDA Implementation Guide that can accommodate the needs described above which could then be further refined to specific genetic testing reports, either realm specific or method-specific or any other set of restrictions. In addition, this IG will strive to serve both research and clinical environment as much as possible. Audience The audience for this document includes software developers and implementers who wish to enable information exchange of genetic testing reports that can be both human readable and machine-processable. Organization of This Guide Templates Templates are organized by document (see Document Templates), by section (see Section Templates), and by clinical statements (see Clinical Statement Templates). Within a section, templates are arranged hierarchically, where a more specific template is nested under the more generic template that it conforms to. See Templates by Containment for a listing of the higher level templates by containment; the appendix Templates Used in This Guide includes a table of all of the templates Organized Hierarchically. Vocabulary and Value Sets Vocabularies recommended in this guide are from standard vocabularies. The LOINC codes developed within the v2 genetic testing results message are used in this IG as optional value sets. When further constraining this IG to the US Realm, it would be possible to mandate the use of these LOINC value sets. Of note, these LOINC codes have been successfully piloted within the clinical genetic laboratory and EHR. In addition, these terms have been added to the NCI-t (U.S. National Cancer Institute's Thesaurus, see: ncit.nci.nih.gov/ Genetic Testing Report (GTR) Page 17

18 INTRODUCTION 18 Use of Templates When valued in an instance, the template identifier (templateid) signals the imposition of a set of templatedefined constraints. The value of this attribute provides a unique identifier for the templates in question. Originator Responsibilities An originator can apply a templateid to assert conformance with a particular template. In the most general forms of CDA exchange, an originator need not apply a templateid for every template that an object in an instance document conforms to. This implementation guide asserts when templateids are required for conformance. Recipient Responsibilities A recipient may reject an instance that does not contain a particular templateid (e.g., a recipient looking to receive only GTR documents can reject an instance without the appropriate templateid). A recipient may process objects in an instance document that do not contain a templateid (e.g., a recipient can process entries that contain Observation acts within a Problems section, even if the entries do not have templateids). Note on Draft Standards The requirements as laid out in the body of this document are subject to change per the policy on implementation guides (see section 13.02" Draft Standard for Trial Use Documents" within the HL7 Governance and Operations Manual, ). Conventions Used in This Guide Conformance Requirements Conformance statements are grouped and identified by the name of the template, along with the templateid and the context of the template (e.g., ClinicalDocument, section, observation), which specifies the element under constraint. If a template is a specialization of another template, its first constraint indicates the more general template. In all cases where a more specific template conforms to a more general template, asserting the more specific template also implies conformance to the more general template. An example is shown below. Template name [<type of template>: templateid <XXXX.XX.XXX.XXX>] Description of the template will be here Conforms to <The template name> Template (templateid: XXXX<XX>XXX>YYY). 2. SHALL contain = <AAA> <code display name> (CodeSystem: <XXX> Class) STATIC (CONF:<number>) Figure 1: Template name and "conforms to" appearance The conformance verb keyword at the start of a constraint ( SHALL, SHOULD, MAY, etc.) indicates business conformance, whereas the cardinality indicator (0..1, 1..1, 1..*, etc.) specifies the allowable occurrences within an instance. Thus, " MAY contain 0..1" and " SHOULD contain 0..1" both allow for a document to omit the particular component, but the latter is a stronger recommendation that the component be included if it is known. The following cardinality indicators may be interpreted as follows: Genetic Testing Report (GTR) Page 18

19 INTRODUCTION as zero to one present 1..1 as one and only one present 2..2 as two must be present 1..* as one or more present 0..* as zero to many present Value set bindings adhere to HL7 Vocabulary Working Group best practices, and include both a conformance verb ( SHALL, SHOULD, MAY, etc.) and an indication of DYNAMIC vs. STATIC binding. The use of SHALL requires that the component be valued with a member from the cited value set; however, in every case any HL7 "null" value such as other (OTH) or unknown (UNK) may be used. Each constraint is uniquely identified (e.g., "CONF:605") by an identifier placed at or near the end of the constraint. These identifiers are not sequential as they are based on the order of creation of the constraint. 1. SHALL contain [1..1] component/structuredbody (CONF:4082). a. This component/structuredbody SHOULD contain [0..1] component (CONF:4130) such that it a. SHALL contain [1..1] Reporting Parameters section (templateid: ) (CONF:4131). b. This component/structuredbody SHALL contain [1..1] component (CONF:4132) such that it a. SHALL contain [1..1] Patient data section - NCR (templateid: ) (CONF:4133). Figure 2: Template-based conformance statements example 1. The value for "Observation in a problem observation SHALL be "EVN" ActMood STATIC. (CONF: 814). 2. A problem observation SHALL include exactly one Observation / statuscode. (CONF: 815). 3. The value for "Observation / statuscode" in a problem observation SHALL be "completed" ActStatus STATIC. (CONF: 816). 4. A problem observation SHOULD contain exactly one Observation / effectivetime, to indicate the biological timing of condition (e.g. the time the condition started, the onset of the illness or symptom, the duration of a condition). (CONF: 817). Figure 3: Conformance statements example (taken from the CCD IG) Keywords The keywords SHALL, SHALL NOT, SHOULD, SHOULD NOT, MAY, and NEED NOT in this document are to be interpreted as described in the HL7 Version 3 Publishing Facilitator's Guide: SHALL: an absolute requirement SHALL NOT: an absolute prohibition against inclusion SHOULD/SHOULD NOT: valid reasons to include or ignore a particular item, but must be understood and carefully weighed MAY/NEED NOT: truly optional; can be included or omitted as the author decides with no implications XML Examples XML samples appear in various figures in this document in a fixed-width font. Portions of the XML content may be omitted from the content for brevity, marked by an ellipsis ( ) as shown in the example below. <ClinicalDocument xmlns= urn:h17-org:v3 >... </ClinicalDocument> Figure 4: ClinicalDocument example Genetic Testing Report (GTR) Page 19

20 INTRODUCTION 20 XPath expressions are used in the narrative and conformance requirements to identify elements because they are familiar to many XML implementers. Contents of the Ballot Package Table 1: Contents of the Ballot Package Filename CDAR2_IG_GENTESTRPT_R1_D2_2012SEP Description This guide CDA Genetic Testing Report (GTR) Samples (.xml files) A GTR sample on hearing loss genetic variation tests; A few more GTR samples are included on DCM, Warfarin and cytogenetics but have not been adjusted to the latest structure, however the differences are minor and they can illustrate the use of GTR in various cases; NOTE: the samples are provided in order to illustrate the GTR structure and are not necessarily accurate content-wise cda.xsl Changes from previous ballot.doc A generic stylesheet for displaying the content of the sample document in HTML A Word document summarizing main changes made after GTR ballot cycles Genetic Testing Report (GTR) Page 20

21 Chapter 2 DOCUMENT TEMPLATES Topics: Genetic Testing Report This section contains the document level constraints for CDA documents that are compliant with this implementation guide.

22 DOCUMENT TEMPLATES 22 Genetic Testing Report [ClinicalDocument: templateid ] The GeneticTestingReport is a document template and thus serves as the root template for the GTR Implementation Guide. Its organization is described in the Approach section of this document. The sub-sections residing here constitute the backbone of the GTR. A specific genetic test is described in the TestDetailsSection which serves as a blueprint specialized sections describing testing like genetic variation or gene expression. 1. SHALL contain exactly one [1..1] code/@code=" " Genetic analysis summary report (CodeSystem: LOINC) (CONF-GTR-1) 2. SHALL contain exactly one [1..1] title (CONF-GTR-7) Default title is "Genetic Testing Report". 3. SHALL contain exactly one [1..1] component a. Contains exactly one [1..1] Summary Section (templateid: ) 4. Contains at least one [1..*] component a. Contains exactly one [1..1] Test Details Section (templateid: ) 5. Contains zero or one [0..1] component a. Contains exactly one [1..1] Test Information Section (templateid: ) 6. Sections and subsections SHALL have a title and the title SHALL NOT be empty. Text of a section title can specialize the section code by being more specific, for example, a hearing loss genetic testing report. 7. Sections SHALL appear in the order they are presented in this guide. Thus, SummarySection which SHALL appear first and TestInformationSection which SHOULD appear last. In between, TestDetailsSection can be repeated per the no. of genetic tests performed. Note that a TestInformationSection can appear in each of the specific test sections. 1. Contains exactly one [1..1] typeid with data type Infrastructure Root Type Id 2. Contains exactly one [1..1] id with data type II 3. SHALL contain exactly one [1..1] code/@code=" " Genetic analysis summary report (CodeSystem: LOINC) (CONF-GTR-1) 4. SHALL contain exactly one [1..1] title (CONF-GTR-7) Default title is "Genetic Testing Report". 5. Contains exactly one [1..1] effectivetime with data type TS 6. Contains exactly one [1..1] confidentialitycode with data type CE 7. Contains at least one [1..*] recordtarget, where its type is Record Target a. Contains exactly one [1..1] Record Target 8. Contains at least one [1..*] author, where its type is Author a. Contains exactly one [1..1] Author 9. Contains exactly one [1..1] custodian, where its type is Custodian a. Contains exactly one [1..1] Custodian 10. Contains exactly one [1..1] component, where its type is Component2 a. Contains exactly one [1..1] Component2 11. SHALL contain exactly one [1..1] component a. Contains exactly one [1..1] Summary Section (templateid: ) 12. Contains at least one [1..*] component a. Contains exactly one [1..1] Test Details Section (templateid: ) 13. Contains zero or one [0..1] component Genetic Testing Report (GTR) Page 22

23 DOCUMENT TEMPLATES 23 a. Contains exactly one [1..1] Test Information Section (templateid: ) 14. Sections and subsections SHALL have a title and the title SHALL NOT be empty. Text of a section title can specialize the section code by being more specific, for example, a hearing loss genetic testing report. 15. Sections SHALL appear in the order they are presented in this guide. Thus, SummarySection which SHALL appear first and TestInformationSection which SHOULD appear last. In between, TestDetailsSection can be repeated per the no. of genetic tests performed. Note that a TestInformationSection can appear in each of the specific test sections. <?xml version="1.0" encoding="utf-8"?> <ClinicalDocument xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd"> <typeid root=" " extension="pocd_hd000040"/> <templateid root=" "/> <id root=" " extension="c266"/> <code code=" " codesystem=" " codesystemname="loinc" displayname="genetic analysis summary report"/> <title>genetic Testing Report</title> <effectivetime value=" "/> <confidentialitycode code="r" codesystem=" "/> <languagecode code="en-us"/> <setid root=" " extension="bb35"/> <versionnumber value="1"/> <recordtarget> <patientrole> <id root=" " extension=" "/> <patient> <name use="l"> <given>john</given> <given>q.</given> <family>doe</family> </name> <administrativegendercode code="m" codesystem=" " codesystemname="administrativegender" displayname="male"/> <birthtime value=" "/> </patient> <providerorganization> <id root=" "/> <name>the New Genetic Testing Laboratory</name> </providerorganization> </patientrole> </recordtarget> <author> <functioncode code="aut" displayname="author (originator)"/> <time/> <assignedauthor> <id root=" " extension="author123"/> <code code="aut" displayname="author"/> <assignedperson> <name>jean Geome</name> </assignedperson> <representedorganization> <id root=" " extension="2dd "/> </representedorganization> </assignedauthor> </author> <custodian> <assignedcustodian> <representedcustodianorganization> <id root=" "/> Genetic Testing Report (GTR) Page 23

24 DOCUMENT TEMPLATES 24 </representedcustodianorganization> </assignedcustodian> </custodian> <legalauthenticator> <time value=" "/> <signaturecode code="s"/> <assignedentity> <id root=" " extension="abcd " displayable="true"/> <code code="aut" displayname="author"/> <assignedperson> <name>jean Genome</name> </assignedperson> <representedorganization> <id root=" " extension="2dd " displayable="true"/> <name>the New Genetic Testing Laboratory</name> </representedorganization> </assignedentity> </legalauthenticator> <documentationof> <serviceevent> <id root=" " extension="abcd-1234"/> </serviceevent> </documentationof> <component> <structuredbody> <component> <section> <templateid root=" "/> <code code=" " codesystem=" " codesystemname="snomed-ct" displayname="summary report"/> <title>summary</title> <component> <section> <templateid root=" "/> <code code=" " codesystem=" " codesystemname="snomed-ct" displayname="indication for"/> <title>indications</title> <text> <list> <content ID="a2">Indication: Profound sensorineural hearing loss</ content> </list> </text> <entry> <templateid root=" "/> <id root=" "/> <code code="mthu008863" codesystem=" " codesystemname="loinc" displayname="indications description"/> <effectivetime value="1950"/> <value xsi:type="cd" code="c26973" codesystemname="nci Thesaurus" displayname="sensory Hearing Loss"/> </entry> </section> </component> <component> <section> <templateid root=" "/> Genetic Testing Report (GTR) Page 24

25 DOCUMENT TEMPLATES 25 <code code=" " codesystem=" " codesystemname="snomed-ct" displayname="specimen description"/> <title>specimen and Genomic Source Class</title> <text> <list> Peripheral Blood Genomic source class: Germline </list> </text> <entry> <templateid root=" "/> <code code=" " codesystemname="loinc" displayname="genomic source class"/> <value xsi:type="cd" code="la6683-2" codesystemname="loinc" displayname="germline"/> <specimen> <templateid root=" "/> <specimenrole> <specimenplayingentity> <code code=" " codesystem=" " codesystemname="snomed-ct" displayname="peripheral blood specimen"/> </specimenplayingentity> </specimenrole> </specimen> </entry> </section> </component> <component> <section> <templateid root=" "/> <code code=" " codesystem=" " codesystemname="snomed-ct" displayname="genetic test"/> <title>summary of Tests Performed</title> <text> <list> <content ID="a1"> GJB2 Full Gene Test <content ID="a5"> GJB6-D13S1830 deletion terminology <content ID="a3"> Mitochondrial Hearing Loss Mutation Test </list> </text> </section> </component> <component> <section> <templateid root=" "/> <code code=" " codesystem=" " codesystemname="snomed-ct" displayname="assessment section"/> <title>overall Interpretation</title> <text> Genetic Testing Report (GTR) Page 25

26 DOCUMENT TEMPLATES 26 <list> <content stylecode="bold">inconclusive. DNA sequencing detected two changes in the GJB2 gene, 79G>A (V27I) and 109G>A (V37I). The V27I change has been reported as a benign variant (references) and is not believed to cause hearing loss. The V37I mutation has been previously reported in patients with hearing loss. This mutation, in homozygosity or combined with another GJB2 disease causing mutation, typically results in a mild to moderate hearing loss (Cryns et al. 2005). Mutations in both copies of the GJB2 gene are necessary to assume that GJB2 is responsible for the hearing loss. Although two mutations were identified in this patient, we would assume that the combination of a benign variant and a mild pathogenic mutation would result in a mild to moderate hearing loss rather than a moderately-severe one, as in this patient. It is most likely that the hearing loss in this patient is the result of the V37I mutation and an unknown second pathogenic mutation. It should be noted that a second mutation is not identified in a large percentage (10-50%) of patients with nonsyndromic hearing loss and GJB2 mutations (del Castillo et al. 2003). GJB6-D13S1830 Deletion: A PCR-based analysis of the GJB6-D13S1830 region of chromosome 13 was performed and did not detect the deletion. This test does not assess the DNA sequence of the GJB6 gene or detect other mutations that could affect the expression of the gene. Mitochondrial Hearing Loss mutations: Targeted bidirectional sequencing of mitochondrial DNA 1555 and 7445 regions did not detect the presence of these mutations. Although this test examines all regions known to contain pathogenic mutations in these genes, it does not include sequencing of the 5' end of the MTRNR1 gene. </list> </text> <entry> <templateid root=" "/> <id root=" "/> <code code=" " codesystemname="loinc" displayname="genetic analysis summary panel"/> <statuscode code="completed"/> <entryrelationship typecode="subj"> <organizer classcode="battery" moodcode="evn"> <statuscode code="completed"/> <component> <id root=" "/> <code/> </component> <component> <id root=" "/> <code/> Genetic Testing Report (GTR) Page 26

27 DOCUMENT TEMPLATES 27 </component> <component> <id root=" "/> <code/> </component> <component> <id root=" "/> <code/> </component> </organizer> <entryrelationship typecode="rson"> <observation classcode="cond" moodcode="evn"> <id root=" "/> <code/> <entryrelationship typecode="sprt"> <observation classcode="obs" moodcode="def"> <templateid root=" "/> <code code=" " codesystemname="loinc" displayname="genetic disease analysis overall interpretation"/> <statuscode code="completed"/> <effectivetime value=" "/> <value xsi:type="cd" code="la9663-1" displayname="inconclusive"/> </entry> </section> </component> <component> <section> <templateid root=" "/> <code code=" " codesystem=" " codesystemname="snomed-ct" displayname="plan section"/> <title>recommendations</title> <text> <list> Although some cases may represent a coincidental carrier state, all of the studies have concluded that there are likely to be other genetic mutations that have not yet been identified. Genetic counseling is recommended for this patient and his/her family members. </list> </text> </section> </component> </section> </component> <component> <section> <templateid root=" "/> <code code=" " codesystem=" " codesystemname="snomed-ct" displayname="report"/> <title>genetic Variations</title> Genetic Testing Report (GTR) Page 27

28 DOCUMENT TEMPLATES 28 <entry> <templateid root=" "/> <id root=" "/> <code code=" " codesystemname="loinc" displayname="dna Analysis Discrete Sequence Variant Panel"/> <statuscode code="completed"/> <effectivetime value=" "/> <entryrelationship typecode="subj"> <code code=" " codesystemname="loinc" displayname="gene Identifier"/> <value xsi:type="cd" code="gjb2" codesystemname="hugo"/> <entryrelationship typecode="subj"> <code code=" " codesystemname="loinc" displayname="transcript Reference Sequence Identifier"/> <value xsi:type="cd" code="nm_ " codesystem="refseq" codesystemname="ncbi Reference Sequence"/> <entryrelationship typecode="subj"> <code code=" " codesystemname="loinc" displayname="dna Sequence Variation Identifier"/> <value xsi:type="cd" code="rs " codesystemname="dbsnp"/> <entryrelationship typecode="subj"> <code code=" " codesystemname="loinc" displayname="dna Sequence Variation"/> <value xsi:type="cd" code="109g>a" codesystemname="hgvs nomenclature for the description of sequence variations"/> <entryrelationship typecode="subj"> <code code=" " codesystemname="loinc" displayname="dna Sequence Variation Type"/> <value xsi:type="cd" code="la6690-7" codesystemname="loinc" displayname="substitution"/> <entryrelationship typecode="subj"> <templateid root=" "/> <code code=" " codesystemname="loinc" displayname="amino Acid Change"/> <value xsi:type="cd" code="val37ile"/> <entryrelationship typecode="subj"> <code code=" " codesystemname="loinc" displayname="amino acid change type"/> <value xsi:type="cd" code="la6698-0" displayname="missense"/> <entryrelationship typecode="subj"> Genetic Testing Report (GTR) Page 28

29 DOCUMENT TEMPLATES 29 <code code=" " codesystemname="loinc" displayname="dna Region Name"/> <value xsi:type="st">exon 2</value> <entryrelationship typecode="subj"> <code code=" " codesystemname="loinc" displayname=" Allelic State"/> <value xsi:type="cd" code="la6705-3" codesystemname="loinc" displayname="homozygous"/> <entryrelationship typecode="rson"> <id root=" "/> <code/> <entryrelationship typecode="sprt"> <observation classcode="obs" moodcode="def"> <code code=" " codesystemname="loinc" displayname="genetic disease sequence variation interpretation"/> <value xsi:type="cd" code="la6668-3" codesystemname="loinc" displayname="pathogenic"/> </entry> <entry> <templateid root=" "/> <id root=" "/> <code code=" " codesystemname="loinc" displayname=" DNA Analysis Discrete Sequence Variant Panel"/> <statuscode code="completed"/> <effectivetime value=" "/> <entryrelationship typecode="subj"> <code code=" " codesystemname="loinc" displayname="gene Identifier"/> <value xsi:type="cd" code="gjb2" codesystemname="hugo"/> <entryrelationship typecode="subj"> <code code=" " codesystemname="loinc" displayname="transcript Reference Sequence Identifier"/> <value xsi:type="cd" code="nm_ " codesystem="refseq" codesystemname="ncbi Reference Sequence"/> <entryrelationship typecode="subj"> <code code=" " codesystemname="loinc" displayname="dna Sequence Variation Identifier"/> <value xsi:type="cd" code="rs " codesystemname="dbsnp"/> <entryrelationship typecode="subj"> Genetic Testing Report (GTR) Page 29

30 DOCUMENT TEMPLATES 30 <code code=" " codesystemname="loinc" displayname="dna Sequence Variation"/> <value xsi:type="cd" code="79g>a" codesystemname="hgvs nomenclature for the description of sequence variations"/> <entryrelationship typecode="subj"> <code code=" " codesystemname="loinc" displayname="dna Sequence Variation Type"/> <value xsi:type="cd" code="la6690-7" codesystemname="loinc" displayname="substitution"/> <entryrelationship typecode="subj"> <code code=" " codesystemname="loinc" displayname="amino Acid Change"/> <value xsi:type="cd" code="val27ile"/> <entryrelationship typecode="subj"> <code code=" " codesystemname="loinc" displayname="amino acid change type"/> <value xsi:type="cd" code="la6698-0" displayname="missense"/> <entryrelationship typecode="subj"> <code code=" " codesystemname="loinc" displayname="dna Region Name"/> <value xsi:type="st">exon 2</value> <entryrelationship typecode="subj"> <code code=" " codesystemname="loinc" displayname=" Allelic State"/> <value xsi:type="cd" code="la6706-1" codesystemname="loinc" displayname="heterozygous"/> <entryrelationship typecode="rson"> <id root=" "/> <code/> <entryrelationship typecode="sprt"> <observation classcode="obs" moodcode="def"> <code code=" " codesystemname="loinc" displayname="genetic disease sequence variation interpretation"/> <value xsi:type="cd" code="la6675-8" codesystemname="loinc" displayname="benign"/> </entry> <component> <section> <templateid root=" "/> Genetic Testing Report (GTR) Page 30

31 DOCUMENT TEMPLATES 31 <code code=" " codesystem=" " codesystemname="snomed-ct" displayname="genetic test"/> <title>tests Performed</title> <text> <list> GJB2 Full Gene Test </list> </text> <entry> <templateid root=" "/> <code displayname="test Performed"/> <statuscode code="completed"/> <effectivetime value=" "/> <value xsi:type="cd" code="cx26full" codesystem=" " codesystemname="loinc" displayname="connexin 26 Full Gene Test"> <originaltext> <reference value="#a1"/> </originaltext> </value> <entryrelationship typecode="rson"> <observation classcode="cond" moodcode="evn"> <id root=" "/> <code/> </entry> </section> </component> <component> <section> <templateid root=" "/> <code code=" " codesystem=" " codesystemname="snomed-ct" displayname="results section"/> <title>findings</title> <text> <list> DNA MUTATIONS: Heterozygous 109G>A (V37I), Exon 2, GJB2, Pathogenic INCIDENTAL VARIANTS: Heterozygous 79G>A (V27I), Exon 2, GJB2, Benign </list> </text> </section> </component> <component> <section> <templateid root=" "/> <code code=" " codesystem=" " codesystemname="snomed-ct" displayname="assessment section"/> <title>interpretation</title> Genetic Testing Report (GTR) Page 31

32 DOCUMENT TEMPLATES 32 <text> <list> Mutations interpretation <list> V37I - Pathogenic V27I - Benign </list> Details: DNA sequencing detected two mutations in the GJB2 gene, 79G>A (V27I) and 109G>A (V37I). The V27I mutation has been reported as a benign variant (references) and is not believed to cause hearing loss. The V37I mutation has been previously reported in patients with hearing loss. This mutation, in homozygosity or combined with another GJB2 disease causing mutation, typically results in a mild to moderate hearing loss (Cryns et al. 2005). Mutations in both copies of the GJB2 gene are necessary to assume that GJB2 is responsible for the hearing loss. Although two mutations were identified in this patient, we would assume that the combination of a benign variant and a mild pathogenic mutation would result in a mild to moderate hearing loss rather than a moderately-severe one, as in this patient. It is most likely that the hearing loss in this patient is the result of the V37I mutation and an unknown second pathogenic mutation. It should be noted that a second mutation is not identified in a large percentage (10-50%) of patients with nonsyndromic hearing loss and GJB2 mutations (del Castillo et al. 2003). </list> </text> </section> </component> </section> </component> <component> <section> <templateid root=" "/> <code code=" " codesystem=" " codesystemname="snomed-ct" displayname="report"/> <title>genetic Variations</title> <entry> <observation classcode="cond" moodcode="evn"> <templateid root=" "/> <id root=" "/> <code code=" " displayname="dna region of interest"/> <statuscode code="completed"/> <effectivetime value=" "/> <value xsi:type="cd" code="gjb6-d13s1830"/> <entryrelationship typecode="comp"> <observation classcode="obs" moodcode="evn" negationind="true"> <code code=" " displayname="dna Sequence Variation type"/> <value xsi:type="cd" code="la6692-3" displayname="deletion"/> </entry> Genetic Testing Report (GTR) Page 32

33 DOCUMENT TEMPLATES 33 <component> <section> <templateid root=" "/> <code code=" " codesystem=" " codesystemname="snomed-ct" displayname="genetic test"/> <title>tests Performed</title> <text> <list> GJB6-D13S1830 Deletion Test </list> </text> <entry> <templateid root=" "/> <code displayname="test Performed"/> <statuscode code="completed"/> <effectivetime value=" "/> <value xsi:type="cd" code="tbd" codesystem=" " codesystemname="loinc" displayname="connexin 30 Deletion Test"> <originaltext> <reference value="#a5"/> </originaltext> </value> <entryrelationship typecode="rson"> <observation classcode="cond" moodcode="evn"> <id root=" "/> <code/> </entry> </section> </component> <component> <section> <templateid root=" "/> <code code=" " codesystem=" " codesystemname="snomed-ct" displayname="results section"/> <title>findings</title> <text> <list> Negative. </list> </text> </section> </component> <component> <section> <templateid root=" "/> <code code=" " codesystem=" " codesystemname="snomed-ct" displayname="assessment section"/> <title>interpretation</title> <text> <list> Genetic Testing Report (GTR) Page 33

34 DOCUMENT TEMPLATES 34 GJB6-D13S1830 Deletion: A PCR-based analysis of the GJB6- D13S1830 region of chromosome 13 was performed and did not detect the deletion. This test does not assess the DNA sequence of the GJB6 gene or detect other mutations that could affect the expression of the gene. </list> </text> </section> </component> </section> </component> <component> <section> <templateid root=" "/> <code code=" " codesystem=" " codesystemname="snomed-ct" displayname="report"/> <title>genetic Variations</title> <entry> <templateid root=" "/> <id root=" "/> <code code=" " displayname="gene identifier"/> <statuscode code="completed"/> <effectivetime value=" "/> <value xsi:type="cd" code="mtts1"/> <entryrelationship typecode="comp"> <observation classcode="obs" moodcode="evn" negationind="true"> <code/> </entry> <entry> <code code=" " displayname="gene identifier"/> <statuscode code="completed"/> <effectivetime value=" "/> <value xsi:type="cd" code="mtrnr1"/> <entryrelationship typecode="comp"> <observation classcode="obs" moodcode="evn" negationind="true"> <code/> </entry> <component> <section> <templateid root=" "/> <code code=" " codesystem=" " codesystemname="snomed-ct" displayname="genetic test"/> <title>tests Performed</title> <text> <list> Mitochondrial Hearing Loss Genes Test </list> </text> Genetic Testing Report (GTR) Page 34

35 DOCUMENT TEMPLATES 35 <entry> <templateid root=" "/> <code displayname="test Performed"/> <statuscode code="completed"/> <effectivetime value=" "/> <value xsi:type="cd" code="tbd" codesystem=" " codesystemname="loinc" displayname="mtts1 and MTRNR1 Genes Test"> <originaltext> <reference value="#a3"/> </originaltext> </value> <entryrelationship typecode="rson"> <observation classcode="cond" moodcode="evn"> <id root=" "/> <code/> </entry> </section> </component> <component> <section> <templateid root=" "/> <code code=" " codesystem=" " codesystemname="snomed-ct" displayname="results section"/> <title>findings</title> <text> <list> Negative. </list> </text> </section> </component> <component> <section> <templateid root=" "/> <code code=" " codesystem=" " codesystemname="snomed-ct" displayname="assessment section"/> <title>interpretation</title> <text> <list> DNA sequencing did not detect the presence of any mutations in the MTTS1 and MTRNR1 genes. Although this test examines all regions known to contain pathogenic mutations in these genes, it does not include sequencing of the 5' end of the MTRNR1 gene. </list> </text> </section> </component> </section> </component> <component> <section> Genetic Testing Report (GTR) Page 35

36 DOCUMENT TEMPLATES 36 <templateid root=" "/> <code code=" " codesystem=" " codesystemname="loinc" displayname="general information section"/> <title>test Information</title> <component> <section> <templateid root=" "/> <code code=" " codesystem=" " codesystemname="loinc" displayname="background information section"/> <title>background</title> <text> <list> Mutations in the GJB2 (connexin 26) gene are the most common cause of non syndromic hearing loss and are most often seen in a person with hearing loss that was found in early childhood without any other medical problems. The severity of the hearing loss can range from mild to profound. The inheritance pattern is usually autosomal recessive, requiring two mutations, one in each copy of the gene, to cause hearing loss. The GJB6- D13S1830 deletion removes most of the GJB6 gene, which encodes the connexin 30 protein (Cx30). This deletion, when present in two copies or when combined with a single connexin 26 mutation, causes hearing loss. Although the frequency of mitochondrial hearing loss is unknown, studies suggest that mitochondrial mutations play an important role in inherited and acquired hearing impairment. </list> </text> </section> </component> <component> <section> <templateid root=" "/> <code code=" " codesystem=" " codesystemname="snomed-ct" displayname="method"/> <title>methodology</title> <text> <list> Exon 1 and the coding region of exon 2 of the connexin 26 (GJB2) gene are amplified using flanking primer sets. PCR products are sequenced using an ABI fluorescence automatic DNA sequencer. This test does not detect large deletions or mutations in non-coding regions that could affect gene expression. This assay is greater than 99.9% accurate in detecting mutations in the sequences analyzed. Polymerase chain reaction (PCR) analysis is performed to detect the presence or absence of a deletion spanning the GJB6-D13S1830 region of chromosome 13. </list> </text> </section> </component> <component> <section> <templateid root=" "/> <code code=" " codesystem=" " codesystemname="loinc" displayname="references section"/> <title>references</title> <text> <list> Genetic Testing Report (GTR) Page 36

37 DOCUMENT TEMPLATES 37 Azaiez H, Chamberlin GP, Fischer SM, Welp CL, Prasad SD, Taggart RT, del Castillo, I, Van Camp G and Smith RJ. GJB2: the spectrum of deafnesscausing allele variants and their phenotype. Hum Mutat. 2004;24(4): Calvo J, Rabionet R, Gasparini P, Estivill X. Connexins and Deafness Homepage. del Castillo I, Moreno-Pelayo MA, del Castillo FJ, Brownstein Z, Marlin S, Adina Q, Cockburn DJ, Pandya A, Siemering KR, Chamberlin GP, Ballana E, Wuyts W, Maciel-Guerra AT, Alvarez A, Villamar M, Shohat M, Abeliovich D, Dahl HH, Estivill X, Gasparini P, Hutchin T, Nance WE, Sartorato EL, Smith RJ, Van Camp G, Avraham KB, Petit C. and Moreno F. Prevalence and evolutionary origins of the del(gjb6-d13s1830) mutation in the DFNB1 locus in hearing-impaired subjects: a multicenter study. Am J Hum Genet. 2003;73: Kelley PM, Harris DJ, Comer BC, Askew JW, Fowler T, Smith SD, Kimberling WJ. Novel mutations in the connexin 26 gene (GJB2) that cause autosomal recessive (DFNB1) hearing loss. Am J Hum Genet Apr;62(4): Kenna MA, Wu BL, Cotanche DA, Korf BR, Rehm HL. Connexin 26 studies in patients with sensorineural hearing loss. Arch Otolaryngol Head Neck Surg Sep;127(9): Kenneson A, Van Naarden Braun K and Boyle C. GJB2 (connexin 26) variants and nonsyndromic sensorineural hearing loss: a HuGE review. Genet Med. 2002;4(4): Park HJ, Hahn SH, Chun YM, Park K, Kim HN. Connexin26 mutations associated with nonsyndromic hearing loss. Laryngoscope Sep;110(9): Rickard S, Kelsell DP, Sirimana T, Rajput K, MacArdle B, Bitner-Glindzicz M. Recurrent mutations in the deafness gene GJB2 (connexin 26) in British Asian families. J Med Genet Aug;38(8): Smith RJH, Van Camp G. Nonsyndromic hearing loss and deafness, DFNB1 (Updated March 14, 2005) In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Genetic Testing Report (GTR) Page 37

38 DOCUMENT TEMPLATES 38 Snoeckx RL, Huygen PLM, Feldmann D, Marlin S, Denoyelle F, Waligora J, Mueller-Malesinska M, Pollak A, Ploski R, Murgia A, Orzan E, Castorina P, Ambrosetti U, Nowakowska-Szyrwinska E, Bal J, Wiszniewski W, Janecke AR, Nekahm-Heis D, Seeman P, Bendova O, Kenna MA, Frangulov A, Rehm HL, Tekin M, Incesulu A, Dahl H-HM, du Sart D, Jenkins L, Lucas D, Bitner-Glindzicz M, Avraham KB, Brownstein Z, del Castillo I, Moreno F, Blin N, Pfister M, Sziklai I, Toth T, Kelley PM, Cohn ES, Maldergem LV, Hilbert P, Roux A-F, Mondain M, Hoefsloot, LH Cremers CWRJ, Lopponen T, Lopponen H, Parving A, Gronskov K, Schrijver I, Roberson J, Gualandi F, Martini A, Lina-Granade G, Pallares-Ruiz N, Correia C, Fialho G, Cryns K, Hilgert N, Van de Heyning P, Nishimura CJ, Smith RJH, and Van Camp G. A genotype-phenotype correlation for GJB2 (connexin 26) deafness. Am J Med Genet 2005 Dec;77(6): </list> </text> </section> </component> </section> </component> </structuredbody> </component> </ClinicalDocument> Figure 5: Genetic Testing Report example Genetic Testing Report (GTR) Page 38

39 Chapter 3 SECTION TEMPLATES Topics: Background Section Findings Section Indications Section Interpretation Section Methodology Section Overall Interpretation Section Performers Section Recommendations Section References Section Specimen Section Summary Of Tests Performed Section Summary Section Test Details Section Test Information Section Test Performed Section

40 SECTION TEMPLATES 40 Background Section [Section: templateid ] The Background Section is a narrative-only section. It nests within the TestInformationSection and its text attribute consists of narrative describing background of the genetic test at stake. 1. MAY contain zero or one [0..1] code (CONF-GTR-18) a. Gtr Background Section MAY contain a code that represents background information supporting the general description of the performed genetic test, e.g., LOINC code , "Background information section". 2. SHALL contain exactly one [1..1] title (CONF-GTR-19) a. Title SHALL contain text that implies "Background information supporting the general description of the performed genetic test(s)" 1. MAY contain zero or one [0..1] code (CONF-GTR-18) a. Gtr Background Section MAY contain a code that represents background information supporting the general description of the performed genetic test, e.g., LOINC code , "Background information section". 2. SHALL contain exactly one [1..1] title (CONF-GTR-19) a. Title SHALL contain text that implies "Background information supporting the general description of the performed genetic test(s)" 3. Title SHALL contain text that implies "Background information supporting the general description of the performed genetic test(s)" 4. Gtr Background Section MAY contain a code that represents background information supporting the general description of the performed genetic test, e.g., LOINC code , "Background information section". <?xml version="1.0" encoding="utf-8"?> <section xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd"> <templateid root=" "/> <code code=" " codesystem=" " codesystemname="loinc" displayname="background information section"/> <title>background</title> <text> <list> Mutations in the GJB2 (connexin 26) gene are the most common cause of non syndromic hearing loss and are most often seen in a person with hearing loss that was found in early childhood without any other medical problems. The severity of the hearing loss can range from mild to profound. The inheritance pattern is usually autosomal recessive, requiring two mutations, one in each copy of the gene, to cause hearing loss. The GJB6- D13S1830 deletion removes most of the GJB6 gene, which encodes the connexin 30 protein (Cx30). This deletion, when present in two copies or when combined with a single connexin 26 mutation, causes hearing loss. Although the frequency of mitochondrial hearing loss is unknown, studies suggest that mitochondrial mutations play an important role in inherited and acquired hearing impairment. </list> </text> </section> Figure 6: Background Section example Genetic Testing Report (GTR) Page 40

41 SECTION TEMPLATES 41 Findings Section [Section: templateid ] The FindingSection is a narrative-only section. It resides within the TestDetailsSection and describe in narrative a specific finding of genetic testing. Note that the structured data is represented in a ClinicalGenomicStatement subtemplates nesting in the Test Details Section sub-templates. 1. MAY contain zero or one [0..1] code (CONF-GTR-47) a. Gtr Findings Section MAY contain a code that represents findings/results of the testing, e.g., SNOMED-CT code= , "Results section". 2. SHALL contain exactly one [1..1] title and SHALL equal "Findings" (CONF-GTR-48) a. Title SHALL contain text that implies "Findings/results of the performed genetic tests". 1. MAY contain zero or one [0..1] code (CONF-GTR-47) a. Gtr Findings Section MAY contain a code that represents findings/results of the testing, e.g., SNOMED-CT code= , "Results section". 2. SHALL contain exactly one [1..1] title and SHALL equal "Findings" (CONF-GTR-48) a. Title SHALL contain text that implies "Findings/results of the performed genetic tests". 3. Title SHALL contain text that implies "Findings/results of the performed genetic tests". 4. Gtr Findings Section MAY contain a code that represents findings/results of the testing, e.g., SNOMED-CT code= , "Results section". <?xml version="1.0" encoding="utf-8"?> <section xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd"> <templateid root=" "/> <code code=" " codesystem=" " codesystemname="snomed-ct" displayname="results section"/> <title>findings</title> <text> <list> DNA MUTATIONS: Heterozygous 109G>A (V37I), Exon 2, GJB2, Pathogenic INCIDENTAL VARIANTS: Heterozygous 79G>A (V27I), Exon 2, GJB2, Benign </list> </text> </section> Figure 7: Findings Section example Indications Section [Section: templateid ] The IndicationSection nests within the TestDetailsSection and its text attribute consists of narrative describing the indication of performing the genetic tests. Common indications for preforming a genetic test often include family history of a familial (or inherited) disease or increased risk of developing a disease. Increasingly, molecular analysis Genetic Testing Report (GTR) Page 41

42 SECTION TEMPLATES 42 of a patient's tumor is another common indication for genetic testing. The IndicationSection may also consist of structured indication observations that shall reference or be referenced from Clinical Genomic Statement instances. 1. MAY contain zero or one [0..1] code (CONF-GTR-10) a. Gtr IndicationsSection MAY contain a code that represents indications of performing the testing. 2. SHALL contain exactly one [1..1] title and SHALL equal "Containing text that means 'Indications'" (CONF- GTR-11) a. Title SHALL contain text that implies "Indications of performing genetic tests" 3. Contains zero or more [0..*] entry a. Contains exactly one [1..1] Indication Observation (templateid: ) 1. MAY contain zero or one [0..1] code (CONF-GTR-10) a. Gtr IndicationsSection MAY contain a code that represents indications of performing the testing. 2. SHALL contain exactly one [1..1] title and SHALL equal "Containing text that means 'Indications'" (CONF- GTR-11) a. Title SHALL contain text that implies "Indications of performing genetic tests" 3. Contains zero or more [0..*] entry a. Contains exactly one [1..1] Indication Observation (templateid: ) 4. Title SHALL contain text that implies "Indications of performing genetic tests" 5. Gtr IndicationsSection MAY contain a code that represents indications of performing the testing. <?xml version="1.0" encoding="utf-8"?> <section xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd"> <templateid root=" "/> <code code=" " codesystem=" " codesystemname="snomed-ct" displayname="indication for"/> <title>indications</title> <text> <list> <content ID="a2">Indication: Profound sensorineural hearing loss</ content> </list> </text> <entry> <templateid root=" "/> <id root=" "/> <code code="mthu008863" codesystem=" " codesystemname="loinc" displayname="indications description"/> <effectivetime value="1950"/> <value xsi:type="cd" code="c26973" codesystemname="nci Thesaurus" displayname="sensory Hearing Loss"/> </entry> </section> Figure 8: Indications Section example Genetic Testing Report (GTR) Page 42

43 SECTION TEMPLATES 43 Interpretation Section [Section: templateid ] The InterpretationSection nests within the TestDetailsSection and its text attribute consists of narrative describing the interpretation of the genetic test results. The InterpretationSection may also consist of structured interprations that shall reference or be referenced from Clinical Genomic Statement instances 1. MAY contain zero or one [0..1] code (CONF-GTR-20) a. Gtr Interpretation Section MAY contain a code that represents interpretations of genetic testing results/ findings. 2. SHALL contain exactly one [1..1] title and SHALL equal "Interpretation" (CONF-GTR-21) a. Title SHALL contain text that implies "Interpretations of genetic testing results/findings" 3. Contains zero or more [0..*] entry a. Contains exactly one [1..1] Interpretive Phenotype (templateid: ) 1. MAY contain zero or one [0..1] code (CONF-GTR-20) a. Gtr Interpretation Section MAY contain a code that represents interpretations of genetic testing results/ findings. 2. SHALL contain exactly one [1..1] title and SHALL equal "Interpretation" (CONF-GTR-21) a. Title SHALL contain text that implies "Interpretations of genetic testing results/findings" 3. Contains zero or more [0..*] entry a. Contains exactly one [1..1] Interpretive Phenotype (templateid: ) 4. Title SHALL contain text that implies "Interpretations of genetic testing results/findings" 5. Gtr Interpretation Section MAY contain a code that represents interpretations of genetic testing results/findings. <?xml version="1.0" encoding="utf-8"?> <section xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd"> <templateid root=" "/> <code code=" " codesystem=" " codesystemname="snomed-ct" displayname="assessment section"/> <title>interpretation</title> <text> <list> Mutations interpretation <list> V37I - Pathogenic V27I - Benign </list> Details: DNA sequencing detected two mutations in the GJB2 gene, 79G>A (V27I) and 109G>A (V37I). The V27I mutation has been reported as a benign variant (references) and is not believed to cause hearing loss. The V37I mutation has been previously reported in patients with hearing loss. This mutation, in homozygosity or combined with another GJB2 disease causing mutation, typically results in a mild to moderate hearing loss (Cryns et al. 2005). Mutations in both copies of the GJB2 gene are necessary to assume that GJB2 is responsible for the hearing loss. Although two Genetic Testing Report (GTR) Page 43

44 SECTION TEMPLATES 44 mutations were identified in this patient, we would assume that the combination of a benign variant and a mild pathogenic mutation would result in a mild to moderate hearing loss rather than a moderately-severe one, as in this patient. It is most likely that the hearing loss in this patient is the result of the V37I mutation and an unknown second pathogenic mutation. It should be noted that a second mutation is not identified in a large percentage (10-50%) of patients with nonsyndromic hearing loss and GJB2 mutations (del Castillo et al. 2003). </list> </text> </section> Figure 9: Interpretation Section example Methodology Section [Section: templateid ] The MethodologySection nests within the TestInformationSection and its text attribute consists of narrative describing methodology of the genetic test at stake. Where possible, use section entries to codify methods used in this genetic tests. Note that LOINC codes are being developed to capture methodology details for sequencing and gene chip tests and might be available in future releases. 1. MAY contain zero or one [0..1] code (CONF-GTR-16) a. Gtr Methodology Section MAY contain a code that represents methodology information about the performed genetic test. 2. SHALL contain exactly one [1..1] title and SHALL equal "Methodology" (CONF-GTR-17) a. Title SHALL contain text that implies "Methodology information about the performed genetic test(s)" 1. MAY contain zero or one [0..1] code (CONF-GTR-16) a. Gtr Methodology Section MAY contain a code that represents methodology information about the performed genetic test. 2. SHALL contain exactly one [1..1] title and SHALL equal "Methodology" (CONF-GTR-17) a. Title SHALL contain text that implies "Methodology information about the performed genetic test(s)" 3. Title SHALL contain text that implies "Methodology information about the performed genetic test(s)" 4. Gtr Methodology Section MAY contain a code that represents methodology information about the performed genetic test. <?xml version="1.0" encoding="utf-8"?> <section xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd"> <templateid root=" "/> <code code=" " codesystem=" " codesystemname="snomed-ct" displayname="method"/> <title>methodology</title> <text> <list> Exon 1 and the coding region of exon 2 of the connexin 26 (GJB2) gene are amplified using flanking primer sets. PCR products are sequenced using an ABI fluorescence automatic DNA sequencer. This test does not detect large deletions or mutations in non-coding regions that could affect gene expression. This assay is greater than 99.9% accurate in detecting mutations in the sequences analyzed. Polymerase chain reaction (PCR) Genetic Testing Report (GTR) Page 44

45 SECTION TEMPLATES 45 analysis is performed to detect the presence or absence of a deletion spanning the GJB6-D13S1830 region of chromosome 13. </list> </text> </section> Figure 10: Methodology Section example Overall Interpretation Section [Section: templateid ] The Overall Interpretive Section describes the overall interpretation of the genetic tests performed. It is further specialized by its sub-templates that represent overall interpretation by various testing types. Note that its own code and value could potentially represent the overall interpretation of multiple overall interpretations in case the report describes multiple tests performed (e.g., genetic variation and gene expression tests). 1. MAY contain zero or one [0..1] code a. Gtr Overall Interpretation Section MAY contain a code that represents an overall interpretation summarizing the interpretations of the various genetic testing results/findings in a GTR Document. 2. SHALL contain exactly one [1..1] title and SHALL equal "Overall Interpretation" (CONF-GTR-36) a. Title SHALL contain text that implies "An overall interpretation summarizing the interpretations of the various genetic testing results/findings in a GTR Document" 3. Contains zero or one [0..1] entry a. Contains exactly one [1..1] Clinical Genomic Statement Overall Interpretation (templateid: ) 1. MAY contain zero or one [0..1] code a. Gtr Overall Interpretation Section MAY contain a code that represents an overall interpretation summarizing the interpretations of the various genetic testing results/findings in a GTR Document. 2. SHALL contain exactly one [1..1] title and SHALL equal "Overall Interpretation" (CONF-GTR-36) a. Title SHALL contain text that implies "An overall interpretation summarizing the interpretations of the various genetic testing results/findings in a GTR Document" 3. Contains zero or one [0..1] entry a. Contains exactly one [1..1] Clinical Genomic Statement Overall Interpretation (templateid: ) 4. Title SHALL contain text that implies "An overall interpretation summarizing the interpretations of the various genetic testing results/findings in a GTR Document" 5. Gtr Overall Interpretation Section MAY contain a code that represents an overall interpretation summarizing the interpretations of the various genetic testing results/findings in a GTR Document. <?xml version="1.0" encoding="utf-8"?> <section xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd"> <templateid root=" "/> <code code=" " codesystem=" " codesystemname="snomed-ct" displayname="assessment section"/> <title>overall Interpretation</title> <text> <list> <content stylecode="bold">inconclusive. Genetic Testing Report (GTR) Page 45

46 SECTION TEMPLATES 46 DNA sequencing detected two changes in the GJB2 gene, 79G>A (V27I) and 109G>A (V37I). The V27I change has been reported as a benign variant (references) and is not believed to cause hearing loss. The V37I mutation has been previously reported in patients with hearing loss. This mutation, in homozygosity or combined with another GJB2 disease causing mutation, typically results in a mild to moderate hearing loss (Cryns et al. 2005). Mutations in both copies of the GJB2 gene are necessary to assume that GJB2 is responsible for the hearing loss. Although two mutations were identified in this patient, we would assume that the combination of a benign variant and a mild pathogenic mutation would result in a mild to moderate hearing loss rather than a moderately-severe one, as in this patient. It is most likely that the hearing loss in this patient is the result of the V37I mutation and an unknown second pathogenic mutation. It should be noted that a second mutation is not identified in a large percentage (10-50%) of patients with nonsyndromic hearing loss and GJB2 mutations (del Castillo et al. 2003). GJB6-D13S1830 Deletion: A PCR-based analysis of the GJB6-D13S1830 region of chromosome 13 was performed and did not detect the deletion. This test does not assess the DNA sequence of the GJB6 gene or detect other mutations that could affect the expression of the gene. Mitochondrial Hearing Loss mutations: Targeted bidirectional sequencing of mitochondrial DNA 1555 and 7445 regions did not detect the presence of these mutations. Although this test examines all regions known to contain pathogenic mutations in these genes, it does not include sequencing of the 5' end of the MTRNR1 gene. </list> </text> <entry> <templateid root=" "/> <id root=" "/> <code code=" " codesystemname="loinc" displayname="genetic analysis summary panel"/> <statuscode code="completed"/> <entryrelationship typecode="subj"> <organizer classcode="battery" moodcode="evn"> <statuscode code="completed"/> <component> <id root=" "/> <code/> </component> <component> <id root=" "/> <code/> </component> <component> <id root=" "/> Genetic Testing Report (GTR) Page 46

47 SECTION TEMPLATES 47 <code/> </component> <component> <id root=" "/> <code/> </component> </organizer> <entryrelationship typecode="rson"> <observation classcode="cond" moodcode="evn"> <id root=" "/> <code/> <entryrelationship typecode="sprt"> <observation classcode="obs" moodcode="def"> <templateid root=" "/> <code code=" " codesystemname="loinc" displayname="genetic disease analysis overall interpretation"/> <statuscode code="completed"/> <effectivetime value=" "/> <value xsi:type="cd" code="la9663-1" displayname="inconclusive"/> </entry> </section> Figure 11: Overall Interpretation Section example Performers Section [Section: templateid ] The PerformersSection nests within the TestDetailsSection and its text attribute consists of narrative describing the performers of the genetic test in case it's different than the performer represented in the GTR header. The PerformersSection may also consist of structured performer data that shall reference or be referenced from Clinical Genomic Statement instances. 1. MAY contain zero or one [0..1] code a. Gtr PerformersSection MAY contain a code that represents the description of performer(s) of the genetic testing". 2. Contains exactly one [1..1] title a. Title SHALL contain text that implies "Performer(s) of the genetic testing" 1. MAY contain zero or one [0..1] code a. Gtr PerformersSection MAY contain a code that represents the description of performer(s) of the genetic testing". 2. Contains exactly one [1..1] title a. Title SHALL contain text that implies "Performer(s) of the genetic testing" 3. Title SHALL contain text that implies "Performer(s) of the genetic testing" 4. Gtr PerformersSection MAY contain a code that represents the description of performer(s) of the genetic testing". <?xml version="1.0" encoding="utf-8"?> Genetic Testing Report (GTR) Page 47

48 SECTION TEMPLATES 48 <section xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd"> <id root="mdht" extension=" "/> <code code=" "/> <title>text FOR TITLE</title> </section> Figure 12: Performers Section example Recommendations Section [Section: templateid ] The RecommendationsSection nests within the SummarySection and describes recommendations such as followup genetic testing, follow-up visits to specialists, recommended actions, etc. It is encouraged to use codified recommended actions as much as possible, e.g., use procedure codes if recommended actions are type of procedures. 1. MAY contain zero or one [0..1] code (CONF-GTR-85) a. Gtr Recommendations Section MAY contain a code that represents recommendations followoing the testing results and interpretations. 2. SHALL contain exactly one [1..1] title and SHALL equal "Recommendations" (CONF-GTR-86) a. Title SHALL contain text that implies "Recommendations following results of the genetic testing and interpretations" 1. MAY contain zero or one [0..1] code (CONF-GTR-85) a. Gtr Recommendations Section MAY contain a code that represents recommendations followoing the testing results and interpretations. 2. SHALL contain exactly one [1..1] title and SHALL equal "Recommendations" (CONF-GTR-86) a. Title SHALL contain text that implies "Recommendations following results of the genetic testing and interpretations" 3. Title SHALL contain text that implies "Recommendations following results of the genetic testing and interpretations" 4. Gtr Recommendations Section MAY contain a code that represents recommendations followoing the testing results and interpretations. <?xml version="1.0" encoding="utf-8"?> <section xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd"> <templateid root=" "/> <code code=" " codesystem=" " codesystemname="snomed-ct" displayname="plan section"/> <title>recommendations</title> <text> <list> Although some cases may represent a coincidental carrier state, all of the studies have concluded that there are likely to be other genetic mutations that have not yet been identified. Genetic counseling is recommended for this patient and his/her family members. </list> </text> </section> Figure 13: Recommendations Section example Genetic Testing Report (GTR) Page 48

49 SECTION TEMPLATES 49 References Section [Section: templateid ] The ReferencesSection section consists of references to scientific literature that supports the description of the test. It nests within the TestInformationSection and its text attribute consists of a narrative describing scientific references of the genetic test, and optionally structured entries representing publications identified through common ids like PubMed ids and OMIM ids. For instance, PubMed id's may be provided as references to peer reviewed journal articles. OMIM id's may be provided to OMIM (Online Mendelian Inheritance in Man) records containing currated information (from peer reviewed literature). 1. MAY contain zero or one [0..1] code (CONF-GTR-14) a. Gtr References Section MAY contain a code that represents scientific references cited by the Background and Methodology sections (e.g., LOINC code , "References section"). 2. SHALL contain exactly one [1..1] title and SHALL equal "References" (CONF-GTR-15) a. Title SHALL contain text that implies "Scientific references cited by the Background and Methodology sections" 1. MAY contain zero or one [0..1] code (CONF-GTR-14) a. Gtr References Section MAY contain a code that represents scientific references cited by the Background and Methodology sections (e.g., LOINC code , "References section"). 2. SHALL contain exactly one [1..1] title and SHALL equal "References" (CONF-GTR-15) a. Title SHALL contain text that implies "Scientific references cited by the Background and Methodology sections" 3. Title SHALL contain text that implies "Scientific references cited by the Background and Methodology sections" 4. Gtr References Section MAY contain a code that represents scientific references cited by the Background and Methodology sections (e.g., LOINC code , "References section"). <?xml version="1.0" encoding="utf-8"?> <section xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd"> <templateid root=" "/> <code code=" " codesystem=" " codesystemname="loinc" displayname="references section"/> <title>references</title> <text> <list> Azaiez H, Chamberlin GP, Fischer SM, Welp CL, Prasad SD, Taggart RT, del Castillo, I, Van Camp G and Smith RJ. GJB2: the spectrum of deafnesscausing allele variants and their phenotype. Hum Mutat. 2004;24(4): Calvo J, Rabionet R, Gasparini P, Estivill X. Connexins and Deafness Homepage. del Castillo I, Moreno-Pelayo MA, del Castillo FJ, Brownstein Z, Marlin S, Adina Q, Cockburn DJ, Pandya A, Siemering KR, Chamberlin GP, Ballana E, Wuyts W, Maciel-Guerra AT, Alvarez A, Villamar M, Shohat M, Abeliovich D, Dahl HH, Estivill X, Gasparini P, Hutchin T, Nance WE, Sartorato EL, Smith RJ, Van Camp G, Avraham KB, Petit C. and Moreno F. Prevalence and Genetic Testing Report (GTR) Page 49

50 SECTION TEMPLATES 50 evolutionary origins of the del(gjb6-d13s1830) mutation in the DFNB1 locus in hearing-impaired subjects: a multicenter study. Am J Hum Genet. 2003;73: Kelley PM, Harris DJ, Comer BC, Askew JW, Fowler T, Smith SD, Kimberling WJ. Novel mutations in the connexin 26 gene (GJB2) that cause autosomal recessive (DFNB1) hearing loss. Am J Hum Genet Apr;62(4): Kenna MA, Wu BL, Cotanche DA, Korf BR, Rehm HL. Connexin 26 studies in patients with sensorineural hearing loss. Arch Otolaryngol Head Neck Surg Sep;127(9): Kenneson A, Van Naarden Braun K and Boyle C. GJB2 (connexin 26) variants and nonsyndromic sensorineural hearing loss: a HuGE review. Genet Med. 2002;4(4): Park HJ, Hahn SH, Chun YM, Park K, Kim HN. Connexin26 mutations associated with nonsyndromic hearing loss. Laryngoscope Sep;110(9): Rickard S, Kelsell DP, Sirimana T, Rajput K, MacArdle B, Bitner-Glindzicz M. Recurrent mutations in the deafness gene GJB2 (connexin 26) in British Asian families. J Med Genet Aug;38(8): Smith RJH, Van Camp G. Nonsyndromic hearing loss and deafness, DFNB1 (Updated March 14, 2005) In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Snoeckx RL, Huygen PLM, Feldmann D, Marlin S, Denoyelle F, Waligora J, Mueller-Malesinska M, Pollak A, Ploski R, Murgia A, Orzan E, Castorina P, Ambrosetti U, Nowakowska-Szyrwinska E, Bal J, Wiszniewski W, Janecke AR, Nekahm-Heis D, Seeman P, Bendova O, Kenna MA, Frangulov A, Rehm HL, Tekin M, Incesulu A, Dahl H-HM, du Sart D, Jenkins L, Lucas D, Bitner-Glindzicz M, Avraham KB, Brownstein Z, del Castillo I, Moreno F, Blin N, Pfister M, Sziklai I, Toth T, Kelley PM, Cohn ES, Maldergem LV, Hilbert P, Roux A-F, Mondain M, Hoefsloot, LH Cremers CWRJ, Lopponen T, Lopponen H, Parving A, Gronskov K, Schrijver I, Roberson J, Gualandi F, Martini A, Lina-Granade G, Pallares-Ruiz N, Correia C, Fialho G, Cryns K, Hilgert N, Van de Heyning P, Nishimura CJ, Smith RJH, and Van Camp G. A genotype-phenotype correlation for GJB2 (connexin 26) deafness. Am J Med Genet 2005 Dec;77(6): </list> </text> Genetic Testing Report (GTR) Page 50

51 SECTION TEMPLATES 51 </section> Figure 14: References Section example Specimen Section [Section: templateid ] The SpecimenSection describes the specimen used for the genetic testing at stake and its genomic source class. The SpecimenSection may also consist of structured specimen data that shall reference or be referenced from Clinical Genomic Statement instances. This section can be placed in the SummarySection if the same specimen was used for all sections or if a general description of the specimen is needed at the summary level. Optionally, this section can reside in each testing section where full details about the specimen can be described. If the specimen section appears on the summary section, then the use of it in each testing section can describe specific extraction / processing done to the original specimen. 1. MAY contain zero or one [0..1] code (CONF-GTR-33) a. Gtr Specimen Section MAY contain a code that represents descriptions of the specimen used in the testing (e.g., SNOMED-CT code , "Specimen description"). 2. SHALL contain exactly one [1..1] title (CONF-GTR-34) a. Title SHALL contain text that implies "Specimen Description" 3. Contains zero or one [0..1] entry a. Contains exactly one [1..1] Genomic Source Class (templateid: ) 1. MAY contain zero or one [0..1] code (CONF-GTR-33) a. Gtr Specimen Section MAY contain a code that represents descriptions of the specimen used in the testing (e.g., SNOMED-CT code , "Specimen description"). 2. SHALL contain exactly one [1..1] title (CONF-GTR-34) a. Title SHALL contain text that implies "Specimen Description" 3. Contains zero or one [0..1] entry a. Contains exactly one [1..1] Genomic Source Class (templateid: ) 4. Title SHALL contain text that implies "Specimen Description" 5. Gtr Specimen Section MAY contain a code that represents descriptions of the specimen used in the testing (e.g., SNOMED-CT code , "Specimen description"). <?xml version="1.0" encoding="utf-8"?> <section xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd"> <templateid root=" "/> <code code=" " codesystem=" " codesystemname="snomed-ct" displayname="specimen description"/> <title>specimen and Genomic Source Class</title> <text> <list> Peripheral Blood Genomic source class: Germline </list> </text> <entry> <templateid root=" "/> <code code=" " codesystemname="loinc" displayname="genomic source class"/> <value xsi:type="cd" code="la6683-2" codesystemname="loinc" displayname="germline"/> Genetic Testing Report (GTR) Page 51

52 SECTION TEMPLATES 52 <specimen> <templateid root=" "/> <specimenrole> <specimenplayingentity> <code code=" " codesystem=" " codesystemname="snomed-ct" displayname="peripheral blood specimen"/> </specimenplayingentity> </specimenrole> </specimen> </entry> </section> Figure 15: Specimen Section example Summary Of Tests Performed Section [Section: templateid ] The SummaryOfTestsPerformedSection nests within the SummarySection and its text attribute consists of concise narrative describing all tests performed and documented in this report. Optionally, it can hold structured data idnetifying the performed tests. It is similar to the TestPerformedSection, but can hold several tests (with concise descriptions) in contrast to the TestPerformedSection residing in each specific testing section and could have more detail about that specific test. 1. MAY contain zero or one [0..1] code a. Gtr Summary Of Tests Performed Section MAY contain a code that represents the summary of all performed genetic testing. 2. SHALL contain exactly one [1..1] title a. Title SHALL contain text that implies "All performed genetic testing" 3. SHALL contain zero or more [0..*] entry a. Contains exactly one [1..1] Test Performed Observation (templateid: ) 1. MAY contain zero or one [0..1] code a. Gtr Summary Of Tests Performed Section MAY contain a code that represents the summary of all performed genetic testing. 2. SHALL contain exactly one [1..1] title a. Title SHALL contain text that implies "All performed genetic testing" 3. SHALL contain zero or more [0..*] entry a. Contains exactly one [1..1] Test Performed Observation (templateid: ) 4. Title SHALL contain text that implies "All performed genetic testing" 5. Gtr Summary Of Tests Performed Section MAY contain a code that represents the summary of all performed genetic testing. Summary Of Tests Performed Section example <?xml version="1.0" encoding="utf-8"?> <section xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd"> <templateid root=" "/> <code code=" " codesystem=" " codesystemname="snomed-ct" displayname="genetic test"/> <title>summary of Tests Performed</title> Genetic Testing Report (GTR) Page 52

53 SECTION TEMPLATES 53 <text> <list> <content ID="a1"> GJB2 Full Gene Test <content ID="a5"> GJB6-D13S1830 deletion terminology <content ID="a3"> Mitochondrial Hearing Loss Mutation Test </list> </text> </section> Summary Section [Section: templateid ] The SummarySection resides at the highest level of the Genetic Testing Report and consists of several sub-sections describing the overall interpretation of the various genetic tests described in the GTR as well as the genomic source type, recommended follow-up genetic tests, specialist visits, and care plan. 1. MAY contain zero or one [0..1] code a. Gtr Summary Section MAY contain a code that represents the summary of all genetic tests described in this document. 2. SHALL contain exactly one [1..1] title a. Title SHALL contain text that implies "Summary of all genetic tests described in this document" 3. SHOULD contain zero or one [0..1] component a. Contains exactly one [1..1] Indications Section (templateid: ) 4. SHOULD contain zero or one [0..1] component a. Contains exactly one [1..1] Summary Of Tests Performed Section (templateid: ) 5. SHOULD contain zero or one [0..1] component a. Contains exactly one [1..1] Overall Interpretation Section (templateid: ) 6. SHOULD contain zero or one [0..1] component a. Contains exactly one [1..1] Recommendations Section (templateid: ) 7. Contains zero or one [0..1] component a. Contains exactly one [1..1] Specimen Section (templateid: ) 8. Sub-sections of the SummarySection SHALL appear in the order presented in this implementation guide. 1. MAY contain zero or one [0..1] code a. Gtr Summary Section MAY contain a code that represents the summary of all genetic tests described in this document. 2. SHALL contain exactly one [1..1] title Genetic Testing Report (GTR) Page 53

54 SECTION TEMPLATES 54 a. Title SHALL contain text that implies "Summary of all genetic tests described in this document" 3. SHOULD contain zero or one [0..1] component a. Contains exactly one [1..1] Indications Section (templateid: ) 4. SHOULD contain zero or one [0..1] component a. Contains exactly one [1..1] Summary Of Tests Performed Section (templateid: ) 5. SHOULD contain zero or one [0..1] component a. Contains exactly one [1..1] Overall Interpretation Section (templateid: ) 6. SHOULD contain zero or one [0..1] component a. Contains exactly one [1..1] Recommendations Section (templateid: ) 7. Contains zero or one [0..1] component a. Contains exactly one [1..1] Specimen Section (templateid: ) 8. Sub-sections of the SummarySection SHALL appear in the order presented in this implementation guide. 9. Title SHALL contain text that implies "Summary of all genetic tests described in this document" 10. Gtr Summary Section MAY contain a code that represents the summary of all genetic tests described in this document. <?xml version="1.0" encoding="utf-8"?> <section xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd"> <templateid root=" "/> <code code=" " codesystem=" " codesystemname="snomed-ct" displayname="summary report"/> <title>summary</title> <component> <section> <templateid root=" "/> <code code=" " codesystem=" " codesystemname="snomed-ct" displayname="indication for"/> <title>indications</title> <text> <list> <content ID="a2">Indication: Profound sensorineural hearing loss</ content> </list> </text> <entry> <templateid root=" "/> <id root=" "/> <code code="mthu008863" codesystem=" " codesystemname="loinc" displayname="indications description"/> <effectivetime value="1950"/> <value xsi:type="cd" code="c26973" codesystemname="nci Thesaurus" displayname="sensory Hearing Loss"/> </entry> </section> </component> <component> <section> <templateid root=" "/> Genetic Testing Report (GTR) Page 54

55 SECTION TEMPLATES 55 <code code=" " codesystem=" " codesystemname="snomed-ct" displayname="specimen description"/> <title>specimen and Genomic Source Class</title> <text> <list> Peripheral Blood Genomic source class: Germline </list> </text> <entry> <templateid root=" "/> <code code=" " codesystemname="loinc" displayname="genomic source class"/> <value xsi:type="cd" code="la6683-2" codesystemname="loinc" displayname="germline"/> <specimen> <templateid root=" "/> <specimenrole> <specimenplayingentity> <code code=" " codesystem=" " codesystemname="snomed-ct" displayname="peripheral blood specimen"/> </specimenplayingentity> </specimenrole> </specimen> </entry> </section> </component> <component> <section> <templateid root=" "/> <code code=" " codesystem=" " codesystemname="snomed-ct" displayname="genetic test"/> <title>summary of Tests Performed</title> <text> <list> <content ID="a1"> GJB2 Full Gene Test <content ID="a5"> GJB6-D13S1830 deletion terminology <content ID="a3"> Mitochondrial Hearing Loss Mutation Test </list> </text> </section> </component> <component> <section> <templateid root=" "/> <code code=" " codesystem=" " codesystemname="snomed-ct" displayname="assessment section"/> <title>overall Interpretation</title> <text> <list> Genetic Testing Report (GTR) Page 55

56 SECTION TEMPLATES 56 <content stylecode="bold">inconclusive. DNA sequencing detected two changes in the GJB2 gene, 79G>A (V27I) and 109G>A (V37I). The V27I change has been reported as a benign variant (references) and is not believed to cause hearing loss. The V37I mutation has been previously reported in patients with hearing loss. This mutation, in homozygosity or combined with another GJB2 disease causing mutation, typically results in a mild to moderate hearing loss (Cryns et al. 2005). Mutations in both copies of the GJB2 gene are necessary to assume that GJB2 is responsible for the hearing loss. Although two mutations were identified in this patient, we would assume that the combination of a benign variant and a mild pathogenic mutation would result in a mild to moderate hearing loss rather than a moderately-severe one, as in this patient. It is most likely that the hearing loss in this patient is the result of the V37I mutation and an unknown second pathogenic mutation. It should be noted that a second mutation is not identified in a large percentage (10-50%) of patients with nonsyndromic hearing loss and GJB2 mutations (del Castillo et al. 2003). GJB6-D13S1830 Deletion: A PCR-based analysis of the GJB6-D13S1830 region of chromosome 13 was performed and did not detect the deletion. This test does not assess the DNA sequence of the GJB6 gene or detect other mutations that could affect the expression of the gene. Mitochondrial Hearing Loss mutations: Targeted bidirectional sequencing of mitochondrial DNA 1555 and 7445 regions did not detect the presence of these mutations. Although this test examines all regions known to contain pathogenic mutations in these genes, it does not include sequencing of the 5' end of the MTRNR1 gene. </list> </text> <entry> <templateid root=" "/> <id root=" "/> <code code=" " codesystemname="loinc" displayname="genetic analysis summary panel"/> <statuscode code="completed"/> <entryrelationship typecode="subj"> <organizer classcode="battery" moodcode="evn"> <statuscode code="completed"/> <component> <id root=" "/> <code/> </component> <component> <id root=" "/> <code/> </component> Genetic Testing Report (GTR) Page 56

57 SECTION TEMPLATES 57 <component> <id root=" "/> <code/> </component> <component> <id root=" "/> <code/> </component> </organizer> <entryrelationship typecode="rson"> <observation classcode="cond" moodcode="evn"> <id root=" "/> <code/> <entryrelationship typecode="sprt"> <observation classcode="obs" moodcode="def"> <templateid root=" "/> <code code=" " codesystemname="loinc" displayname="genetic disease analysis overall interpretation"/> <statuscode code="completed"/> <effectivetime value=" "/> <value xsi:type="cd" code="la9663-1" displayname="inconclusive"/> </entry> </section> </component> <component> <section> <templateid root=" "/> <code code=" " codesystem=" " codesystemname="snomed-ct" displayname="plan section"/> <title>recommendations</title> <text> <list> Although some cases may represent a coincidental carrier state, all of the studies have concluded that there are likely to be other genetic mutations that have not yet been identified. Genetic counseling is recommended for this patient and his/her family members. </list> </text> </section> </component> </section> Figure 16: Summary Section example Genetic Testing Report (GTR) Page 57

58 SECTION TEMPLATES 58 Test Details Section [Section: templateid ] The TestDetailsSection is the blueprint for all specialized sections that describe specific types of genetic testing, such as the genetic variation section, cytogenetic section, etc. It consists sub-sections common in genetic testing, e.g., specimen, indications, tests performed, and test information. In later releases of the GTR, it could be that specialized sections with unique requirements will be created by extending the TestDetailsSection. Note that the interpretation section is narrative only and the structured interpretation appear as part of the clinical genomic statement. 1. MAY contain zero or one [0..1] code a. Gtr Test Details Section MAY contain a code that represents "Detailed report of a specific genetic testing", e.g., Genetic Variations, Cytogenetics, Gene Expression, etc. 2. SHOULD contain zero or one [0..1] title and SHALL equal "Genetic testing report" a. Title SHALL contain text that implies "Detailed report of a specific genetic testing", e.g., Genetic Variations, Cytogenetics, Gene Expression, etc. 3. Contains zero or more [0..*] entry a. Contains exactly one [1..1] Clinical Genomic Statement Cytogenetics (templateid: ) 4. Contains zero or more [0..*] entry a. Contains exactly one [1..1] Clinical Genomic Statement Gene Expression (templateid: ) 5. Contains zero or more [0..*] entry a. Contains exactly one [1..1] Clinical Genomic Statement Genetic Variation (templateid: ) 6. Contains zero or more [0..*] entry a. Contains exactly one [1..1] Clinical Genomic Statement (templateid: ) 7. Contains zero or one [0..1] component a. Contains exactly one [1..1] Indications Section (templateid: ) 8. Contains zero or one [0..1] component a. Contains exactly one [1..1] Test Performed Section (templateid: ) 9. Contains zero or one [0..1] component a. Contains exactly one [1..1] Findings Section (templateid: ) 10. Contains zero or one [0..1] component a. Contains exactly one [1..1] Interpretation Section (templateid: ) 11. Contains zero or one [0..1] component a. Contains exactly one [1..1] Test Information Section (templateid: ) 12. Contains zero or one [0..1] component a. Contains exactly one [1..1] Performers Section (templateid: ) 13. Contains zero or one [0..1] component a. Contains exactly one [1..1] Specimen Section (templateid: ) 14. Sub-sections of the TestDetailsSection SHALL appear in the order presented in this implementation guide. 1. MAY contain zero or one [0..1] code Genetic Testing Report (GTR) Page 58

59 SECTION TEMPLATES 59 a. Gtr Test Details Section MAY contain a code that represents "Detailed report of a specific genetic testing", e.g., Genetic Variations, Cytogenetics, Gene Expression, etc. 2. SHOULD contain zero or one [0..1] title and SHALL equal "Genetic testing report" a. Title SHALL contain text that implies "Detailed report of a specific genetic testing", e.g., Genetic Variations, Cytogenetics, Gene Expression, etc. 3. Contains zero or more [0..*] entry a. Contains exactly one [1..1] Clinical Genomic Statement Cytogenetics (templateid: ) 4. Contains zero or more [0..*] entry a. Contains exactly one [1..1] Clinical Genomic Statement Gene Expression (templateid: ) 5. Contains zero or more [0..*] entry a. Contains exactly one [1..1] Clinical Genomic Statement Genetic Variation (templateid: ) 6. Contains zero or one [0..1] component a. Contains exactly one [1..1] Indications Section (templateid: ) 7. Contains zero or one [0..1] component a. Contains exactly one [1..1] Test Performed Section (templateid: ) 8. Contains zero or one [0..1] component a. Contains exactly one [1..1] Findings Section (templateid: ) 9. Contains zero or one [0..1] component a. Contains exactly one [1..1] Interpretation Section (templateid: ) 10. Contains zero or one [0..1] component a. Contains exactly one [1..1] Test Information Section (templateid: ) 11. Contains zero or one [0..1] component a. Contains exactly one [1..1] Performers Section (templateid: ) 12. Contains zero or one [0..1] component a. Contains exactly one [1..1] Specimen Section (templateid: ) 13. Sub-sections of the TestDetailsSection SHALL appear in the order presented in this implementation guide. 14. Title SHALL contain text that implies "Detailed report of a specific genetic testing", e.g., Genetic Variations, Cytogenetics, Gene Expression, etc. 15. Gtr Test Details Section MAY contain a code that represents "Detailed report of a specific genetic testing", e.g., Genetic Variations, Cytogenetics, Gene Expression, etc. <?xml version="1.0" encoding="utf-8"?> <section xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd"> <id root="mdht" extension=" "/> <code code=" "/> <title>text FOR TITLE</title> <entry> <observation> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> Genetic Testing Report (GTR) Page 59

60 SECTION TEMPLATES 60 <entryrelationship> <observation> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <entryrelationship> <observation> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <entryrelationship> <observation> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <entryrelationship> <observation> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <entryrelationship> <observation> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <entryrelationship> <observation> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> </entry> <entry> <observation> Genetic Testing Report (GTR) Page 60

61 SECTION TEMPLATES 61 <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <entryrelationship> <observation> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <entryrelationship> <observation> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <entryrelationship> <observation> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> </entry> <entry> <observation> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <entryrelationship> <observation> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <entryrelationship> <observation> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> Genetic Testing Report (GTR) Page 61

62 SECTION TEMPLATES 62 <entryrelationship> <observation> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <entryrelationship> <observation> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <entryrelationship> <observation> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <entryrelationship> <observation> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <entryrelationship> <observation> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> </entry> <entry> <observation> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <entryrelationship> <observation> Genetic Testing Report (GTR) Page 62

63 SECTION TEMPLATES 63 <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <entryrelationship> <observation> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <entryrelationship> <observation> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <specimen/> </entry> <component> <section> <id root="mdht" extension=" "/> <code code=" "/> <title>text FOR TITLE</title> <entry> <observation> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> </entry> </section> </component> <component> <section> <id root="mdht" extension=" "/> <code code=" "/> <title>text FOR TITLE</title> <entry> <observation> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> </entry> </section> Genetic Testing Report (GTR) Page 63

64 SECTION TEMPLATES 64 </component> <component> <section> <id root="mdht" extension=" "/> <code code=" "/> <title>text FOR TITLE</title> </section> </component> <component> <section> <id root="mdht" extension=" "/> <code code=" "/> <title>text FOR TITLE</title> <entry> <observation> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> </entry> </section> </component> <component> <section> <id root="mdht" extension=" "/> <code code=" "/> <title>text FOR TITLE</title> <component> <section> <id root="mdht" extension=" "/> <code code=" "/> <title>text FOR TITLE</title> </section> </component> <component> <section> <id root="mdht" extension=" "/> <code code=" "/> <title>text FOR TITLE</title> </section> </component> <component> <section> <id root="mdht" extension=" "/> <code code=" "/> <title>text FOR TITLE</title> </section> </component> </section> </component> <component> <section> <id root="mdht" extension=" "/> <code code=" "/> <title>text FOR TITLE</title> </section> </component> <component> <section> <id root="mdht" extension=" "/> <code code=" "/> Genetic Testing Report (GTR) Page 64

65 SECTION TEMPLATES 65 <title>text FOR TITLE</title> <entry> <observation> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <specimen/> </entry> </section> </component> </section> Figure 17: Test Details Section example Test Information Section [Section: templateid ] The TestInformationSection nests within the TestDetailsSection and its sub-sections consist of narratives describing information on the genetic tests and corresponding structured data. 1. MAY contain zero or one [0..1] code (CONF-GTR-45) a. Gtr Test Information Section MAY contain a code that represents general description of the performed genetic tests (e.g., LOINC code , "General information section"). 2. SHALL contain exactly one [1..1] title (CONF-GTR-46) a. Title SHALL contain text that implies "General description of the performed genetic test(s)" 3. MAY contain zero or one [0..1] component a. Contains exactly one [1..1] Background Section (templateid: ) 4. MAY contain zero or one [0..1] component a. Contains exactly one [1..1] Methodology Section (templateid: ) 5. MAY contain zero or one [0..1] component a. Contains exactly one [1..1] References Section (templateid: ) 1. MAY contain zero or one [0..1] code (CONF-GTR-45) a. Gtr Test Information Section MAY contain a code that represents general description of the performed genetic tests (e.g., LOINC code , "General information section"). 2. SHALL contain exactly one [1..1] title (CONF-GTR-46) a. Title SHALL contain text that implies "General description of the performed genetic test(s)" 3. MAY contain zero or one [0..1] component a. Contains exactly one [1..1] Background Section (templateid: ) 4. MAY contain zero or one [0..1] component a. Contains exactly one [1..1] Methodology Section (templateid: ) 5. MAY contain zero or one [0..1] component a. Contains exactly one [1..1] References Section (templateid: ) 6. Title SHALL contain text that implies "General description of the performed genetic test(s)" Genetic Testing Report (GTR) Page 65

66 SECTION TEMPLATES Gtr Test Information Section MAY contain a code that represents general description of the performed genetic tests (e.g., LOINC code , "General information section"). <?xml version="1.0" encoding="utf-8"?> <section xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd"> <templateid root=" "/> <code code=" " codesystem=" " codesystemname="loinc" displayname="general information section"/> <title>test Information</title> <component> <section> <templateid root=" "/> <code code=" " codesystem=" " codesystemname="loinc" displayname="background information section"/> <title>background</title> <text> <list> Mutations in the GJB2 (connexin 26) gene are the most common cause of non syndromic hearing loss and are most often seen in a person with hearing loss that was found in early childhood without any other medical problems. The severity of the hearing loss can range from mild to profound. The inheritance pattern is usually autosomal recessive, requiring two mutations, one in each copy of the gene, to cause hearing loss. The GJB6- D13S1830 deletion removes most of the GJB6 gene, which encodes the connexin 30 protein (Cx30). This deletion, when present in two copies or when combined with a single connexin 26 mutation, causes hearing loss. Although the frequency of mitochondrial hearing loss is unknown, studies suggest that mitochondrial mutations play an important role in inherited and acquired hearing impairment. </list> </text> </section> </component> <component> <section> <templateid root=" "/> <code code=" " codesystem=" " codesystemname="snomed-ct" displayname="method"/> <title>methodology</title> <text> <list> Exon 1 and the coding region of exon 2 of the connexin 26 (GJB2) gene are amplified using flanking primer sets. PCR products are sequenced using an ABI fluorescence automatic DNA sequencer. This test does not detect large deletions or mutations in non-coding regions that could affect gene expression. This assay is greater than 99.9% accurate in detecting mutations in the sequences analyzed. Polymerase chain reaction (PCR) analysis is performed to detect the presence or absence of a deletion spanning the GJB6-D13S1830 region of chromosome 13. </list> </text> </section> </component> <component> Genetic Testing Report (GTR) Page 66

67 SECTION TEMPLATES 67 <section> <templateid root=" "/> <code code=" " codesystem=" " codesystemname="loinc" displayname="references section"/> <title>references</title> <text> <list> Azaiez H, Chamberlin GP, Fischer SM, Welp CL, Prasad SD, Taggart RT, del Castillo, I, Van Camp G and Smith RJ. GJB2: the spectrum of deafnesscausing allele variants and their phenotype. Hum Mutat. 2004;24(4): Calvo J, Rabionet R, Gasparini P, Estivill X. Connexins and Deafness Homepage. del Castillo I, Moreno-Pelayo MA, del Castillo FJ, Brownstein Z, Marlin S, Adina Q, Cockburn DJ, Pandya A, Siemering KR, Chamberlin GP, Ballana E, Wuyts W, Maciel-Guerra AT, Alvarez A, Villamar M, Shohat M, Abeliovich D, Dahl HH, Estivill X, Gasparini P, Hutchin T, Nance WE, Sartorato EL, Smith RJ, Van Camp G, Avraham KB, Petit C. and Moreno F. Prevalence and evolutionary origins of the del(gjb6-d13s1830) mutation in the DFNB1 locus in hearing-impaired subjects: a multicenter study. Am J Hum Genet. 2003;73: Kelley PM, Harris DJ, Comer BC, Askew JW, Fowler T, Smith SD, Kimberling WJ. Novel mutations in the connexin 26 gene (GJB2) that cause autosomal recessive (DFNB1) hearing loss. Am J Hum Genet Apr;62(4): Kenna MA, Wu BL, Cotanche DA, Korf BR, Rehm HL. Connexin 26 studies in patients with sensorineural hearing loss. Arch Otolaryngol Head Neck Surg Sep;127(9): Kenneson A, Van Naarden Braun K and Boyle C. GJB2 (connexin 26) variants and nonsyndromic sensorineural hearing loss: a HuGE review. Genet Med. 2002;4(4): Park HJ, Hahn SH, Chun YM, Park K, Kim HN. Connexin26 mutations associated with nonsyndromic hearing loss. Laryngoscope Sep;110(9): Rickard S, Kelsell DP, Sirimana T, Rajput K, MacArdle B, Bitner-Glindzicz M. Recurrent mutations in the deafness gene GJB2 (connexin 26) in British Asian families. J Med Genet Aug;38(8): Genetic Testing Report (GTR) Page 67

68 SECTION TEMPLATES 68 Smith RJH, Van Camp G. Nonsyndromic hearing loss and deafness, DFNB1 (Updated March 14, 2005) In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Snoeckx RL, Huygen PLM, Feldmann D, Marlin S, Denoyelle F, Waligora J, Mueller-Malesinska M, Pollak A, Ploski R, Murgia A, Orzan E, Castorina P, Ambrosetti U, Nowakowska-Szyrwinska E, Bal J, Wiszniewski W, Janecke AR, Nekahm-Heis D, Seeman P, Bendova O, Kenna MA, Frangulov A, Rehm HL, Tekin M, Incesulu A, Dahl H-HM, du Sart D, Jenkins L, Lucas D, Bitner-Glindzicz M, Avraham KB, Brownstein Z, del Castillo I, Moreno F, Blin N, Pfister M, Sziklai I, Toth T, Kelley PM, Cohn ES, Maldergem LV, Hilbert P, Roux A-F, Mondain M, Hoefsloot, LH Cremers CWRJ, Lopponen T, Lopponen H, Parving A, Gronskov K, Schrijver I, Roberson J, Gualandi F, Martini A, Lina-Granade G, Pallares-Ruiz N, Correia C, Fialho G, Cryns K, Hilgert N, Van de Heyning P, Nishimura CJ, Smith RJH, and Van Camp G. A genotype-phenotype correlation for GJB2 (connexin 26) deafness. Am J Med Genet 2005 Dec;77(6): </list> </text> </section> </component> </section> Figure 18: Test Information Section example Test Performed Section [Section: templateid ] The TestPerformedSection nests within the TestDetailsSection and its text attribute consists of a narrative describing the tests performed including those which did not have any genetic findings (e.g., no mutations identified within the region examined). It can consist of structured entries describing the performed tests. In priciple, this section should describe a single test, however, multiple observations can be populated to allow for proper description of a composite test. 1. MAY contain zero or one [0..1] code (CONF-GTR-12) a. Gtr Test Performed Section MAY contain a code that represents listing of genetic testing performed. 2. SHALL contain exactly one [1..1] title and SHALL equal "Tests Performed" (CONF-GTR-13) a. Title SHALL contain text that implies "Genetic testing performed" 3. SHOULD contain zero or more [0..*] entry a. Contains exactly one [1..1] Test Performed Observation (templateid: ) 1. MAY contain zero or one [0..1] code (CONF-GTR-12) a. Gtr Test Performed Section MAY contain a code that represents listing of genetic testing performed. 2. SHALL contain exactly one [1..1] title and SHALL equal "Tests Performed" (CONF-GTR-13) a. Title SHALL contain text that implies "Genetic testing performed" 3. SHOULD contain zero or more [0..*] entry Genetic Testing Report (GTR) Page 68

69 SECTION TEMPLATES 69 a. Contains exactly one [1..1] Test Performed Observation (templateid: ) 4. Title SHALL contain text that implies "Genetic testing performed" 5. Gtr Test Performed Section MAY contain a code that represents listing of genetic testing performed. Test Performed Section example <?xml version="1.0" encoding="utf-8"?> <section xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd"> <templateid root=" "/> <code code=" " codesystem=" " codesystemname="snomed-ct" displayname="genetic test"/> <title>tests Performed</title> <text> <list> GJB2 Full Gene Test </list> </text> <entry> <templateid root=" "/> <code displayname="test Performed"/> <statuscode code="completed"/> <effectivetime value=" "/> <value xsi:type="cd" code="cx26full" codesystem=" " codesystemname="loinc" displayname="connexin 26 Full Gene Test"> <originaltext> <reference value="#a1"/> </originaltext> </value> <entryrelationship typecode="rson"> <observation classcode="cond" moodcode="evn"> <id root=" "/> <code/> </entry> </section> Genetic Testing Report (GTR) Page 69

70 SECTION TEMPLATES 70 Genetic Testing Report (GTR) Page 70

71 Chapter 4 CLINICAL STATEMENT TEMPLATES Topics: Clinical Genomic Statement Clinical Genomic Statement Cytogenetics Clinical Genomic Statement Gene Expression Clinical Genomic Statement Genetic Variation Clinical Genomic Statement Overall Interpretation Cytogenetics Associated Observation Cells Analyzed Count Cytogenetics Associated Observation Cells Count Cytogenetics Associated Observation Cells Karyotyped Count Cytogenetics Associated Observation Colonies Count Cytogenetics Associated Observation ISCN Band Level Genetic Variation Associated Observation Amino Acid Change Genetic Variation Associated Observation DNA Change Genetic Variation Associated Observation DNA Region Name Genetic Variation Associated Observation Zygosity Genomic Associated Observation Genomic Observation Reference Genomic Observations Organizer Genomic Source Class Indication Observation This section of the Implementation Guide details the clinical statement entries referenced in the document section templates. The clinical statement entry templates are arranged alphabetically.

72 CLINICAL STATEMENT TEMPLATES 72 Interpretive Phenotype Interpretive Phenotype Cytogenetics Interpretive Phenotype Gene Expression Interpretive Phenotype Genetic Variation Interpretive Phenotype Pharmacogenomic Interpretive Phenotype Pharmacogenomic Drug Efficacy Interpretive Phenotype Pharmacogenomic Drug Metabolism Overall Interpretive Phenotype Chromosome Analysis Overall Interpretive Phenotype Genetic Disease Overall Interpretive Phenotype Genetic Disease Carrier Overall Interpretive Phenotype Pharmacogenomic Drug Efficacy Overall Interpretive Phenotype Pharmacogenomic Drug Metabolism Test Performed Observation Genetic Testing Report (GTR) Page 72

73 CLINICAL STATEMENT TEMPLATES 73 Clinical Genomic Statement [Observation: templateid ] The ClinicalGenomicStatement template serves the structured portion of the GTR Implementation Guide. At its core, there is a genetic observation finding (result), e.g., a genetic variation, which can be associated with an indication for performing this genetic observation, as well as be associated with the interpretation of the observation finding. In addtion, it is possible to associate a specimen and genomic source class with the core genetic finding as well as performers of the genetic observation. Due to the complexity of the interpretation of genetic observations, this template disallows the use of the interpretationcode attribute, rather uses an association to InterpretivePhenotype. Nevertheless, due to the specificity of the interpretation, sub-templates of this template further constrain it by using InterpretivePhenotype sub-templates. For example, ClinicalGenomicStatementGeneticVariation is a sub-template of ClinicalGenomicStatement and is associated with InterpretivePhenotypeGeneticVariation which is a sub-template of InterpretivePhenotype. All clinical genomic statement (CGS) structured data items shall be part of CGS instances so that parsing applications can find the full semantics explicitly represented in one coherent structure. Sub-sections such as Indications, Interpretations and Specimen are mainly for presenting narrative, but they may also contain structured data. In this way, it is possible to have less redundant documents, e.g., in the case where all tests reported in a GTR document have the same indication, an Indications section in the Summary section consists of a full-blown indication observation which all CGS indication observations reference. CGS structured data may point to the respective narrative in sub-sections (by means of XML ID). 1. SHOULD contain zero or one [0..1] entryrelationship a. RSON b. Contains exactly one [1..1] Indication Observation (templateid: ) 2. SHOULD contain zero or one [0..1] entryrelationship a. SPRT b. Contains exactly one [1..1] Interpretive Phenotype (templateid: ) 3. SHOULD contain zero or one [0..1] entryrelationship a. SUBJ b. Contains exactly one [1..1] Genomic Source Class (templateid: ) 4. Contains exactly one [1..1] code 5. Contains zero or more [0..*] value 1. Contains exactly one with data type ActClassObservation 2. Contains exactly one with data type x_actmooddocumentobservation 3. Contains exactly one [1..1] code 4. Contains zero or more [0..*] value 5. SHOULD contain zero or one [0..1] entryrelationship a. RSON b. Contains exactly one [1..1] Indication Observation (templateid: ) 6. SHOULD contain zero or one [0..1] entryrelationship a. SPRT b. Contains exactly one [1..1] Interpretive Phenotype (templateid: ) 7. SHOULD contain zero or one [0..1] entryrelationship a. SUBJ Genetic Testing Report (GTR) Page 73

74 CLINICAL STATEMENT TEMPLATES 74 b. Contains exactly one [1..1] Genomic Source Class (templateid: ) <?xml version="1.0" encoding="utf-8"?> <observation xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd" classcode="obs" moodcode="evn"> <templateid root=" "/> <id root=" "/> <code code=" " codesystemname="loinc" displayname="dna Analysis Discrete Sequence Variant Panel"/> <statuscode code="completed"/> <effectivetime value=" "/> <entryrelationship typecode="subj"> <code code=" " codesystemname="loinc" displayname="gene Identifier"/> <value xsi:type="cd" code="gjb2" codesystemname="hugo"/> <entryrelationship typecode="subj"> <code code=" " codesystemname="loinc" displayname="transcript Reference Sequence Identifier"/> <value xsi:type="cd" code="nm_ " codesystem="refseq" codesystemname="ncbi Reference Sequence"/> <entryrelationship typecode="subj"> <code code=" " codesystemname="loinc" displayname="dna Sequence Variation Identifier"/> <value xsi:type="cd" code="rs " codesystemname="dbsnp"/> <entryrelationship typecode="subj"> <code code=" " codesystemname="loinc" displayname="dna Sequence Variation"/> <value xsi:type="cd" code="109g>a" codesystemname="hgvs nomenclature for the description of sequence variations"/> <entryrelationship typecode="subj"> <code code=" " codesystemname="loinc" displayname="dna Sequence Variation Type"/> <value xsi:type="cd" code="la6690-7" codesystemname="loinc" displayname="substitution"/> <entryrelationship typecode="subj"> <templateid root=" "/> <code code=" " codesystemname="loinc" displayname="amino Acid Change"/> <value xsi:type="cd" code="val37ile"/> <entryrelationship typecode="subj"> <code code=" " codesystemname="loinc" displayname="amino acid change type"/> <value xsi:type="cd" code="la6698-0" displayname="missense"/> Genetic Testing Report (GTR) Page 74

75 CLINICAL STATEMENT TEMPLATES 75 <entryrelationship typecode="subj"> <code code=" " codesystemname="loinc" displayname="dna Region Name"/> <value xsi:type="st">exon 2</value> <entryrelationship typecode="subj"> <code code=" " codesystemname="loinc" displayname=" Allelic State"/> <value xsi:type="cd" code="la6705-3" codesystemname="loinc" displayname="homozygous"/> <entryrelationship typecode="rson"> <id root=" "/> <code/> <entryrelationship typecode="sprt"> <observation classcode="obs" moodcode="def"> <code code=" " codesystemname="loinc" displayname="genetic disease sequence variation interpretation"/> <value xsi:type="cd" code="la6668-3" codesystemname="loinc" displayname="pathogenic"/> Figure 19: Clinical Genomic Statement example Clinical Genomic Statement Cytogenetics [Observation: templateid ] The ClinicalGenomicStatementCytogenetics template is a sub-template of ClinicalGenomicStatement. It is used by the TestDetailsSection to carry the structured data that is unique to cytogenetics. It further constrains the InterpretivePhenotypeObservation abstract template by associating to the InterpretivePhenotypeObservationCytogenetics. 1. SHALL conform to Clinical Genomic Statement template (templateid: ) 2. MAY contain zero or one [0..1] entryrelationship a. Contains exactly one [1..1] Interpretive Phenotype Cytogenetics (templateid: ) 3. SHOULD contain zero or one [0..1] entryrelationship a. Contains exactly one [1..1] Cytogenetics Associated Observation Cells Analyzed Count (templateid: ) 4. SHOULD contain zero or one [0..1] entryrelationship a. Contains exactly one [1..1] Cytogenetics Associated Observation Cells Count (templateid: ) 5. SHOULD contain zero or one [0..1] entryrelationship a. Contains exactly one [1..1] Cytogenetics Associated Observation Cells Karyotyped Count (templateid: ) Genetic Testing Report (GTR) Page 75

76 CLINICAL STATEMENT TEMPLATES SHOULD contain zero or one [0..1] entryrelationship a. Contains exactly one [1..1] Cytogenetics Associated Observation Colonies Count (templateid: ) 7. SHOULD contain zero or one [0..1] entryrelationship a. Contains exactly one [1..1] Cytogenetics Associated Observation ISCN Band Level (templateid: ) 8. Contains exactly one [1..1] code 9. Contains zero or more [0..*] value 10. value SHALL be assigned a string composed using the expression syntax of International System for Human Cytogenetics Nomenclature (ISCN). 1. SHALL conform to Clinical Genomic Statement template (templateid: ) 2. Contains exactly one with data type ActClassObservation 3. Contains exactly one with data type x_actmooddocumentobservation 4. Contains exactly one [1..1] code 5. Contains zero or more [0..*] value 6. SHOULD contain zero or one [0..1] entryrelationship a. RSON b. Contains exactly one [1..1] Indication Observation (templateid: ) 7. SHOULD contain zero or one [0..1] entryrelationship a. SUBJ b. Contains exactly one [1..1] Genomic Source Class (templateid: ) 8. MAY contain zero or one [0..1] entryrelationship a. Contains exactly one [1..1] Interpretive Phenotype Cytogenetics (templateid: ) 9. SHOULD contain zero or one [0..1] entryrelationship a. Contains exactly one [1..1] Cytogenetics Associated Observation Cells Analyzed Count (templateid: ) 10. SHOULD contain zero or one [0..1] entryrelationship a. Contains exactly one [1..1] Cytogenetics Associated Observation Cells Count (templateid: ) 11. SHOULD contain zero or one [0..1] entryrelationship a. Contains exactly one [1..1] Cytogenetics Associated Observation Cells Karyotyped Count (templateid: ) 12. SHOULD contain zero or one [0..1] entryrelationship a. Contains exactly one [1..1] Cytogenetics Associated Observation Colonies Count (templateid: ) 13. SHOULD contain zero or one [0..1] entryrelationship a. Contains exactly one [1..1] Cytogenetics Associated Observation ISCN Band Level (templateid: ) 14. value SHALL be assigned a string composed using the expression syntax of International System for Human Cytogenetics Nomenclature (ISCN). <?xml version="1.0" encoding="utf-8"?> <observation xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd"> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> Genetic Testing Report (GTR) Page 76

77 CLINICAL STATEMENT TEMPLATES 77 <high value="2012"/> </effectivetime> <entryrelationship> <observation> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <entryrelationship> <observation> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <entryrelationship> <observation> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <entryrelationship> <observation> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <entryrelationship> <observation> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <entryrelationship> <observation> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> Genetic Testing Report (GTR) Page 77

78 CLINICAL STATEMENT TEMPLATES 78 Figure 20: Clinical Genomic Statement Cytogenetics example Clinical Genomic Statement Gene Expression [Observation: templateid ] The ClinicalGenomicStatementGeneExpression template is a sub-template of ClinicalGenomicStatement. It is used by the TestDetailsSection to carry the structured data that is unique to gene expression. It further constrains the InterpretivePhenotypeObservation abstract template by associating to the InterpretivePhenotypeObservationGeneExpression. This template is not constrained as the genetic variation and cytogenetics are, due to the rapid developments in the field of gene expression. As much as possible, assign commonly-used codes in the gene expression field into the code and value attributes of this template. 1. SHALL conform to Clinical Genomic Statement template (templateid: ) 2. SHOULD contain exactly one [1..1] code, where SHOULD be selected from (CodeSystem: HUGO Gene Names) (CONF-GTR-68) 3. Contains zero or one [0..1] value 4. MAY contain zero or one [0..1] entryrelationship a. Contains exactly one [1..1] Interpretive Phenotype Gene Expression (templateid: ) 5. MAY contain zero or one [0..1] entryrelationship a. Contains exactly one [1..1] Interpretive Phenotype Pharmacogenomic Drug Efficacy (templateid: ) 6. MAY contain zero or one [0..1] entryrelationship a. Contains exactly one [1..1] Interpretive Phenotype Pharmacogenomic Drug Metabolism (templateid: ) 1. SHALL conform to Clinical Genomic Statement template (templateid: ) 2. Contains exactly one with data type ActClassObservation 3. Contains exactly one with data type x_actmooddocumentobservation 4. SHOULD contain exactly one [1..1] code, where SHOULD be selected from (CodeSystem: HUGO Gene Names) (CONF-GTR-68) 5. Contains zero or one [0..1] value 6. SHOULD contain zero or one [0..1] entryrelationship a. RSON b. Contains exactly one [1..1] Indication Observation (templateid: ) 7. SHOULD contain zero or one [0..1] entryrelationship a. SUBJ b. Contains exactly one [1..1] Genomic Source Class (templateid: ) 8. MAY contain zero or one [0..1] entryrelationship a. Contains exactly one [1..1] Interpretive Phenotype Gene Expression (templateid: ) 9. MAY contain zero or one [0..1] entryrelationship a. Contains exactly one [1..1] Interpretive Phenotype Pharmacogenomic Drug Efficacy (templateid: ) 10. MAY contain zero or one [0..1] entryrelationship Genetic Testing Report (GTR) Page 78

79 CLINICAL STATEMENT TEMPLATES 79 a. Contains exactly one [1..1] Interpretive Phenotype Pharmacogenomic Drug Metabolism (templateid: ) <?xml version="1.0" encoding="utf-8"?> <observation xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd"> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <entryrelationship> <observation> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <entryrelationship> <observation> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <entryrelationship> <observation> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> Figure 21: Clinical Genomic Statement Gene Expression example Clinical Genomic Statement Genetic Variation [Observation: templateid ] The ClinicalGenomicStatementGeneticVariation template is a sub-template of ClinicalGenomicStatement. It is used by TestDetailsSection to carry the structured data that is unique to genetic variations. It is associated with InterpretivePhenotypeObservation sub-templates. 1. SHALL conform to Clinical Genomic Statement template (templateid: ) 2. SHALL contain exactly one [1..1] code (CONF-GTR-90) In principle, the code attribute should designate the type of the genetic variation being described in this Clinical Genomic Statement. Typically, a genetic variation can be characterized by multiple aspects, e.g., DNA change, amino acid change, Transcript Reference Sequence Identifier, etc. It is important to note that Genetic Testing Report (GTR) Page 79

80 CLINICAL STATEMENT TEMPLATES 80 there is no single standard for any type of genetic variation and even HGVS nomenclature doesn't cover all cases. Also, 'gene-centric' variation notations might be disadvantageous because in some genomic locations, a variant may be influencing several genes (or transcripts of the same gene) and may have different effects, for example, an indel in an intron of one transcript may be a frame shift in an exon another transcript for the same gene. When possible, a coded panel of such characteristics should be used, for example, the LOINC panel "DNA Analysis Discrete Sequence Variant Panel" (code= ) designed for clinical environment. When this code is assigned to the code attribute, then this Clinical Genomic Statement SHALL consist of nesting observations describing the Gene Identifier, Transcript Reference Sequence Identifier, DNA Sequence Variation, DNA Sequence Variation Type, Amino Acid Change, Amino Acid Change Type, DNA Region Name, Allelic State, Genomic Source Class. The constraining of these nesting observations are described in detail in the associations of this Clinical Genomic Statement, including their code and binding value sets. If code is not assigned with the above-mentioned LOINC Panel, then it should use either the Human Genome Variation Society (HGVS) nomenclature (identified as HGNC with OID = ) or other recognized notation of genetic variations (TBD). 3. SHOULD contain zero or one [0..1] value (CONF-GTR-55) Please refer to the code attribute documentation. a. If code= (LOINC code for "DNA Analysis Discrete Sequence Variant Panel"), then value SHALL NOT be used. (CONF-GTR-91) 4. MAY contain zero or one [0..1] entryrelationship a. COMP b. Contains exactly one [1..1] Interpretive Phenotype Genetic Variation (templateid: ) 5. MAY contain zero or one [0..1] entryrelationship a. COMP b. Contains exactly one [1..1] Interpretive Phenotype Pharmacogenomic Drug Efficacy (templateid: ) 6. MAY contain zero or one [0..1] entryrelationship a. COMP b. Contains exactly one [1..1] Interpretive Phenotype Pharmacogenomic Drug Metabolism (templateid: ) 7. SHOULD contain zero or one [0..1] entryrelationship a. Contains exactly one [1..1] Genetic Variation Associated Observation Amino Acid Change (templateid: ) 8. SHOULD contain zero or one [0..1] entryrelationship a. Contains exactly one [1..1] Genetic Variation Associated Observation DNA Change (templateid: ) 9. SHOULD contain zero or one [0..1] entryrelationship a. Contains exactly one [1..1] Genetic Variation Associated Observation DNA Region Name (templateid: ) 10. SHOULD contain zero or one [0..1] entryrelationship a. Contains exactly one [1..1] Genetic Variation Associated Observation Zygosity (templateid: ) 1. SHALL conform to Clinical Genomic Statement template (templateid: ) 2. Contains exactly one with data type ActClassObservation 3. Contains exactly one with data type x_actmooddocumentobservation 4. SHALL contain exactly one [1..1] code (CONF-GTR-90) Genetic Testing Report (GTR) Page 80

81 CLINICAL STATEMENT TEMPLATES 81 In principle, the code attribute should designate the type of the genetic variation being described in this Clinical Genomic Statement. Typically, a genetic variation can be characterized by multiple aspects, e.g., DNA change, amino acid change, Transcript Reference Sequence Identifier, etc. It is important to note that there is no single standard for any type of genetic variation and even HGVS nomenclature doesn't cover all cases. Also, 'gene-centric' variation notations might be disadvantageous because in some genomic locations, a variant may be influencing several genes (or transcripts of the same gene) and may have different effects, for example, an indel in an intron of one transcript may be a frame shift in an exon another transcript for the same gene. When possible, a coded panel of such characteristics should be used, for example, the LOINC panel "DNA Analysis Discrete Sequence Variant Panel" (code= ) designed for clinical environment. When this code is assigned to the code attribute, then this Clinical Genomic Statement SHALL consist of nesting observations describing the Gene Identifier, Transcript Reference Sequence Identifier, DNA Sequence Variation, DNA Sequence Variation Type, Amino Acid Change, Amino Acid Change Type, DNA Region Name, Allelic State, Genomic Source Class. The constraining of these nesting observations are described in detail in the associations of this Clinical Genomic Statement, including their code and binding value sets. If code is not assigned with the above-mentioned LOINC Panel, then it should use either the Human Genome Variation Society (HGVS) nomenclature (identified as HGNC with OID = ) or other recognized notation of genetic variations (TBD). 5. SHOULD contain zero or one [0..1] value (CONF-GTR-55) a. If code= (LOINC code for "DNA Analysis Discrete Sequence Variant Panel"), then value SHALL NOT be used. (CONF-GTR-91) Please refer to the code attribute documentation. 6. SHOULD contain zero or one [0..1] entryrelationship a. RSON b. Contains exactly one [1..1] Indication Observation (templateid: ) 7. SHOULD contain zero or one [0..1] entryrelationship a. SUBJ b. Contains exactly one [1..1] Genomic Source Class (templateid: ) 8. MAY contain zero or one [0..1] entryrelationship a. COMP b. Contains exactly one [1..1] Interpretive Phenotype Genetic Variation (templateid: ) 9. MAY contain zero or one [0..1] entryrelationship a. COMP b. Contains exactly one [1..1] Interpretive Phenotype Pharmacogenomic Drug Efficacy (templateid: ) 10. MAY contain zero or one [0..1] entryrelationship a. COMP b. Contains exactly one [1..1] Interpretive Phenotype Pharmacogenomic Drug Metabolism (templateid: ) 11. SHOULD contain zero or one [0..1] entryrelationship a. Contains exactly one [1..1] Genetic Variation Associated Observation Amino Acid Change (templateid: ) 12. SHOULD contain zero or one [0..1] entryrelationship a. Contains exactly one [1..1] Genetic Variation Associated Observation DNA Change (templateid: ) 13. SHOULD contain zero or one [0..1] entryrelationship Genetic Testing Report (GTR) Page 81

82 CLINICAL STATEMENT TEMPLATES 82 a. Contains exactly one [1..1] Genetic Variation Associated Observation DNA Region Name (templateid: ) 14. SHOULD contain zero or one [0..1] entryrelationship a. Contains exactly one [1..1] Genetic Variation Associated Observation Zygosity (templateid: ) 15. If code= (LOINC code for "DNA Analysis Discrete Sequence Variant Panel"), then value SHALL NOT be used. (CONF-GTR-91) <?xml version="1.0" encoding="utf-8"?> <observation xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd" classcode="obs" moodcode="evn"> <templateid root=" "/> <id root=" "/> <code code=" " codesystemname="loinc" displayname="dna Analysis Discrete Sequence Variant Panel"/> <statuscode code="completed"/> <effectivetime value=" "/> <entryrelationship typecode="subj"> <code code=" " codesystemname="loinc" displayname="gene Identifier"/> <value xsi:type="cd" code="gjb2" codesystemname="hugo"/> <entryrelationship typecode="subj"> <code code=" " codesystemname="loinc" displayname="transcript Reference Sequence Identifier"/> <value xsi:type="cd" code="nm_ " codesystem="refseq" codesystemname="ncbi Reference Sequence"/> <entryrelationship typecode="subj"> <code code=" " codesystemname="loinc" displayname="dna Sequence Variation Identifier"/> <value xsi:type="cd" code="rs " codesystemname="dbsnp"/> <entryrelationship typecode="subj"> <code code=" " codesystemname="loinc" displayname="dna Sequence Variation"/> <value xsi:type="cd" code="109g>a" codesystemname="hgvs nomenclature for the description of sequence variations"/> <entryrelationship typecode="subj"> <code code=" " codesystemname="loinc" displayname="dna Sequence Variation Type"/> <value xsi:type="cd" code="la6690-7" codesystemname="loinc" displayname="substitution"/> <entryrelationship typecode="subj"> <templateid root=" "/> <code code=" " codesystemname="loinc" displayname="amino Acid Change"/> Genetic Testing Report (GTR) Page 82

83 CLINICAL STATEMENT TEMPLATES 83 <value xsi:type="cd" code="val37ile"/> <entryrelationship typecode="subj"> <code code=" " codesystemname="loinc" displayname="amino acid change type"/> <value xsi:type="cd" code="la6698-0" displayname="missense"/> <entryrelationship typecode="subj"> <code code=" " codesystemname="loinc" displayname="dna Region Name"/> <value xsi:type="st">exon 2</value> <entryrelationship typecode="subj"> <code code=" " codesystemname="loinc" displayname=" Allelic State"/> <value xsi:type="cd" code="la6705-3" codesystemname="loinc" displayname="homozygous"/> <entryrelationship typecode="rson"> <id root=" "/> <code/> <entryrelationship typecode="sprt"> <observation classcode="obs" moodcode="def"> <code code=" " codesystemname="loinc" displayname="genetic disease sequence variation interpretation"/> <value xsi:type="cd" code="la6668-3" codesystemname="loinc" displayname="pathogenic"/> Figure 22: Clinical Genomic Statement Genetic Variation example Clinical Genomic Statement Overall Interpretation [Observation: templateid ] The ClinicalGenomicStatementOverallInterpretation template is a sub-template of ClinicalGenomicStatement. It is used by theoverallinterpretationsection to carry overall interpretation of all genomic observations in a GTR document. The asscoaited GenomicObservationsOrganizer has references to genomic observations in the GTR document. 1. SHALL conform to Clinical Genomic Statement template (templateid: ) 2. Contains zero or one [0..1] entryrelationship a. Contains exactly one [1..1] Overall Interpretive Phenotype Chromosome Analysis (templateid: ) 3. Contains zero or one [0..1] entryrelationship a. Contains exactly one [1..1] Overall Interpretive Phenotype Genetic Disease (templateid: ) Genetic Testing Report (GTR) Page 83

84 CLINICAL STATEMENT TEMPLATES Contains zero or one [0..1] entryrelationship a. Contains exactly one [1..1] Overall Interpretive Phenotype Genetic Disease Carrier (templateid: ) 5. Contains zero or one [0..1] entryrelationship a. Contains exactly one [1..1] Overall Interpretive Phenotype Pharmacogenomic Drug Efficacy (templateid: ) 6. Contains zero or one [0..1] entryrelationship a. Contains exactly one [1..1] Overall Interpretive Phenotype Pharmacogenomic Drug Metabolism (templateid: ) 7. Contains zero or one [0..1] entryrelationship a. Contains exactly one [1..1] Genomic Observations Organizer (templateid: ) 1. SHALL conform to Clinical Genomic Statement template (templateid: ) 2. Contains exactly one with data type ActClassObservation 3. Contains exactly one with data type x_actmooddocumentobservation 4. Contains exactly one [1..1] code 5. Contains zero or more [0..*] value 6. SHOULD contain zero or one [0..1] entryrelationship a. RSON b. Contains exactly one [1..1] Indication Observation (templateid: ) 7. SHOULD contain zero or one [0..1] entryrelationship a. SUBJ b. Contains exactly one [1..1] Genomic Source Class (templateid: ) 8. Contains zero or one [0..1] entryrelationship a. Contains exactly one [1..1] Overall Interpretive Phenotype Chromosome Analysis (templateid: ) 9. Contains zero or one [0..1] entryrelationship a. Contains exactly one [1..1] Overall Interpretive Phenotype Genetic Disease (templateid: ) 10. Contains zero or one [0..1] entryrelationship a. Contains exactly one [1..1] Overall Interpretive Phenotype Genetic Disease Carrier (templateid: ) 11. Contains zero or one [0..1] entryrelationship a. Contains exactly one [1..1] Overall Interpretive Phenotype Pharmacogenomic Drug Efficacy (templateid: ) 12. Contains zero or one [0..1] entryrelationship a. Contains exactly one [1..1] Overall Interpretive Phenotype Pharmacogenomic Drug Metabolism (templateid: ) 13. Contains zero or one [0..1] entryrelationship a. Contains exactly one [1..1] Genomic Observations Organizer (templateid: ) <?xml version="1.0" encoding="utf-8"?> <observation xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd" classcode="obs" moodcode="evn"> <templateid root=" "/> <id root=" "/> Genetic Testing Report (GTR) Page 84

85 CLINICAL STATEMENT TEMPLATES 85 <code code=" " codesystemname="loinc" displayname="genetic analysis summary panel"/> <statuscode code="completed"/> <entryrelationship typecode="subj"> <organizer classcode="battery" moodcode="evn"> <statuscode code="completed"/> <component> <id root=" "/> <code/> </component> <component> <id root=" "/> <code/> </component> <component> <id root=" "/> <code/> </component> <component> <id root=" "/> <code/> </component> </organizer> <entryrelationship typecode="rson"> <observation classcode="cond" moodcode="evn"> <id root=" "/> <code/> <entryrelationship typecode="sprt"> <observation classcode="obs" moodcode="def"> <templateid root=" "/> <code code=" " codesystemname="loinc" displayname="genetic disease analysis overall interpretation"/> <statuscode code="completed"/> <effectivetime value=" "/> <value xsi:type="cd" code="la9663-1" displayname="inconclusive"/> Figure 23: Clinical Genomic Statement Overall Interpretation example Cytogenetics Associated Observation Cells Analyzed Count [Observation: templateid ] The ClinicalGenomicStatementCytogeneticsCellsAnalyzedCount template is a sub-template of ClinicalGenomicStatementCytogenetics and is used to carry the no. of cells analyzed in a cytogenetics test. 1. SHALL conform to Genomic Associated Observation template (templateid: ) Genetic Testing Report (GTR) Page 85

86 CLINICAL STATEMENT TEMPLATES MAY contain exactly one [1..1] Cells analyzed [#] in Blood or Tissue by Molecular genetics method (CodeSystem: LOINC) 3. MAY contain zero or one [0..1] value with data type INT 1. SHALL conform to Genomic Associated Observation template (templateid: ) 2. Contains exactly one with data type ActClassObservation 3. Contains exactly one with data type x_actmooddocumentobservation 4. MAY contain exactly one [1..1] Cells analyzed [#] in Blood or Tissue by Molecular genetics method (CodeSystem: LOINC) 5. MAY contain zero or one [0..1] value with data type INT 6. Contains zero or more [0..*] methodcode 7. SHALL satisfy: GenomicAssociatedObservation shall be associated with a GenomicObservation within a ClinicalGenomicStatement. <?xml version="1.0" encoding="utf-8"?> <observation xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd"> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <value xsi:type="int" value="1"/> Figure 24: Cytogenetics Associated Observation Cells Analyzed Count example Cytogenetics Associated Observation Cells Count [Observation: templateid ] The ClinicalGenomicStatementCytogeneticsCellsCount template is a sub-template of ClinicalGenomicStatementCytogenetics and is used to carry the no. of cells counted in a cytogenetics test. 1. SHALL conform to Genomic Associated Observation template (templateid: ) 2. MAY contain exactly one [1..1] code/@code=" " Cells counted [#] in Blood or Tissue by Molecular genetics method (CodeSystem: LOINC) 3. SHALL contain zero or one [0..1] value with data type INT 1. SHALL conform to Genomic Associated Observation template (templateid: ) 2. Contains exactly one with data type ActClassObservation 3. Contains exactly one with data type x_actmooddocumentobservation 4. MAY contain exactly one [1..1] code/@code=" " Cells counted [#] in Blood or Tissue by Molecular genetics method (CodeSystem: LOINC) 5. SHALL contain zero or one [0..1] value with data type INT 6. Contains zero or more [0..*] methodcode 7. SHALL satisfy: GenomicAssociatedObservation shall be associated with a GenomicObservation within a ClinicalGenomicStatement. <?xml version="1.0" encoding="utf-8"?> <observation xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd"> Genetic Testing Report (GTR) Page 86

87 CLINICAL STATEMENT TEMPLATES 87 <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <value xsi:type="int" value="1"/> Figure 25: Cytogenetics Associated Observation Cells Count example Cytogenetics Associated Observation Cells Karyotyped Count [Observation: templateid ] The ClinicalGenomicStatementCytogeneticsCellsKaryotypedCount template is a sub-template of ClinicalGenomicStatement and is used to carry the no. of cells karyotyped in a cytogenetics test. 1. SHALL conform to Genomic Associated Observation template (templateid: ) 2. MAY contain exactly one [1..1] code/@code=" " Cells karyotyped.total [#] in Blood (CodeSystem: LOINC) 3. SHALL contain zero or one [0..1] value with data type INT 1. SHALL conform to Genomic Associated Observation template (templateid: ) 2. Contains exactly one with data type ActClassObservation 3. Contains exactly one with data type x_actmooddocumentobservation 4. MAY contain exactly one [1..1] code/@code=" " Cells karyotyped.total [#] in Blood (CodeSystem: LOINC) 5. SHALL contain zero or one [0..1] value with data type INT 6. Contains zero or more [0..*] methodcode 7. SHALL satisfy: GenomicAssociatedObservation shall be associated with a GenomicObservation within a ClinicalGenomicStatement. <?xml version="1.0" encoding="utf-8"?> <observation xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd"> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <value xsi:type="int" value="1"/> Figure 26: Cytogenetics Associated Observation Cells Karyotyped Count example Cytogenetics Associated Observation Colonies Count [Observation: templateid ] The ClinicalGenomicStatementCytogeneticsColoniesCount template is a sub-template of ClinicalGenomicStatement and is used to carry the no. of colonies counted a cytogenetics test. Colony is a discrete focus of cells that is harvested and stained while attached to the cell culture growth substrate. Genetic Testing Report (GTR) Page 87

88 CLINICAL STATEMENT TEMPLATES SHALL conform to Genomic Associated Observation template (templateid: ) 2. MAY contain exactly one [1..1] Colonies counted [#] in Blood or Tissue by Molecular genetics method (CodeSystem: LOINC) 3. SHALL contain zero or one [0..1] value with data type INT 1. SHALL conform to Genomic Associated Observation template (templateid: ) 2. Contains exactly one with data type ActClassObservation 3. Contains exactly one with data type x_actmooddocumentobservation 4. MAY contain exactly one [1..1] Colonies counted [#] in Blood or Tissue by Molecular genetics method (CodeSystem: LOINC) 5. SHALL contain zero or one [0..1] value with data type INT 6. Contains zero or more [0..*] methodcode 7. SHALL satisfy: GenomicAssociatedObservation shall be associated with a GenomicObservation within a ClinicalGenomicStatement. <?xml version="1.0" encoding="utf-8"?> <observation xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd"> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <value xsi:type="int" value="1"/> Figure 27: Cytogenetics Associated Observation Colonies Count example Cytogenetics Associated Observation ISCN Band Level [Observation: templateid ] The ClinicalGenomicStatementCytogeneticsISCNBandLevel template is a sub-template of ClinicalGenomicStatement and is used to carry the ISCN band level of the cytogenetics test. 1. SHALL conform to Genomic Associated Observation template (templateid: ) 2. MAY contain exactly one [1..1] code/@code=" " ISCN band level (CodeSystem: LOINC) 3. MAY contain zero or one [0..1] value with data type CD, where SHALL be selected from ValueSet ISCN band level STATIC a. GTR ClinicalGenomicStatementCytogeneticsISCNBandLevel (self) SHALL satisfy: If self.code@code= (LOINC code for ISCN band level), then self.value@code SHALL be drawn from the LOINC Value Set (ISCN band level in Blood or Tissue by Molecular genetics: ). 1. SHALL conform to Genomic Associated Observation template (templateid: ) 2. Contains exactly one with data type ActClassObservation 3. Contains exactly one with data type x_actmooddocumentobservation 4. MAY contain exactly one [1..1] code/@code=" " ISCN band level (CodeSystem: LOINC) Genetic Testing Report (GTR) Page 88

89 CLINICAL STATEMENT TEMPLATES MAY contain zero or one [0..1] value with data type CD, where SHALL be selected from ValueSet ISCN band level STATIC a. GTR ClinicalGenomicStatementCytogeneticsISCNBandLevel (self) SHALL satisfy: If (LOINC code for ISCN band level), then SHALL be drawn from the LOINC Value Set (ISCN band level in Blood or Tissue by Molecular genetics: ). 6. Contains zero or more [0..*] methodcode 7. SHALL satisfy: GenomicAssociatedObservation shall be associated with a GenomicObservation within a ClinicalGenomicStatement. 8. GTR ClinicalGenomicStatementCytogeneticsISCNBandLevel (self) SHALL satisfy: If self.code@code= (LOINC code for ISCN band level), then self.value@code SHALL be drawn from the LOINC Value Set (ISCN band level in Blood or Tissue by Molecular genetics: ). <?xml version="1.0" encoding="utf-8"?> <observation xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd"> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <value xsi:type="cd" code=" "/> Figure 28: Cytogenetics Associated Observation ISCN Band Level example Genetic Variation Associated Observation Amino Acid Change [Observation: templateid ] The ClinicalGenomicStatementGeneticVariationAminoAcid template is a sub-template of ClinicalGenomicStatement and is used to carry the amino acid change of that genetic variation. 1. SHALL conform to Genomic Associated Observation template (templateid: ) 2. MAY contain exactly one [1..1] code/@code=" " Amino acid change type (CodeSystem: LOINC) (CONF-GTR-60) 3. MAY contain zero or one [0..1] value with data type CD (CONF-GTR-61), where SHALL be selected from ValueSet Amino acid change type STATIC a. GTR ClinicalGenomicStatementGeneticVariationAminoAcidChange (self) SHALL satisfy: If self.code@code= (LOINC code for Amino acid change type), then self.value@code SHALL be drawn from the LOINC Value Set (Amino acid change type: ) (CONF-GTR-59) 4. SHALL satisfy: Either "DNA Change" observation or "Amino Acid Change" observation is required but both may be specified. 1. SHALL conform to Genomic Associated Observation template (templateid: ) 2. Contains exactly one with data type ActClassObservation 3. Contains exactly one with data type x_actmooddocumentobservation 4. MAY contain exactly one [1..1] code/@code=" " Amino acid change type (CodeSystem: LOINC) (CONF-GTR-60) 5. MAY contain zero or one [0..1] value with data type CD (CONF-GTR-61), where SHALL be selected from ValueSet Amino acid change type STATIC Genetic Testing Report (GTR) Page 89

90 CLINICAL STATEMENT TEMPLATES 90 a. GTR ClinicalGenomicStatementGeneticVariationAminoAcidChange (self) SHALL satisfy: If (LOINC code for Amino acid change type), then SHALL be drawn from the LOINC Value Set (Amino acid change type: ) (CONF-GTR-59) 6. Contains zero or more [0..*] methodcode 7. SHALL satisfy: GenomicAssociatedObservation shall be associated with a GenomicObservation within a ClinicalGenomicStatement. 8. GTR ClinicalGenomicStatementGeneticVariationAminoAcidChange (self) SHALL satisfy: If self.code@code= (LOINC code for Amino acid change type), then self.value@code SHALL be drawn from the LOINC Value Set (Amino acid change type: ) (CONF-GTR-59) 9. SHALL satisfy: Either "DNA Change" observation or "Amino Acid Change" observation is required but both may be specified. <?xml version="1.0" encoding="utf-8"?> <observation xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd" classcode="obs" moodcode="evn"> <templateid root=" "/> <code code=" " codesystemname="loinc" displayname="amino Acid Change"/> <value xsi:type="cd" code="val37ile"/> Figure 29: Genetic Variation Associated Observation Amino Acid Change example Genetic Variation Associated Observation DNA Change [Observation: templateid ] The ClinicalGenomicStatementGeneticVariationDNAChange template is a sub-template of ClinicalGenomicStatement and is used to carry the DNA change of that genetic variation. 1. SHALL conform to Genomic Associated Observation template (templateid: ) 2. MAY contain exactly one [1..1] code/@code=" " DNA sequence variation type (CodeSystem: LOINC) (CONF-GTR-57) 3. MAY contain zero or one [0..1] value with data type CD (CONF-GTR-58), where SHALL be selected from ValueSet DNA sequence variation change type STATIC a. GTR ClinicalGenomicStatementGeneticVariationDNAChange (self) SHALL satisfy: If self.code@code= (LOINC code for DNA sequence variation type), then self.value.code SHALL be drawn from the LOINC Value Set (DNA sequence variation type: ). (CONF-GTR-56) 4. SHALL satisfy: Either "DNA Change" observation or "Amino Acid Change" observation is required but both may be specified. 1. SHALL conform to Genomic Associated Observation template (templateid: ) 2. Contains exactly one with data type ActClassObservation 3. Contains exactly one with data type x_actmooddocumentobservation 4. MAY contain exactly one [1..1] code/@code=" " DNA sequence variation type (CodeSystem: LOINC) (CONF-GTR-57) Genetic Testing Report (GTR) Page 90

91 CLINICAL STATEMENT TEMPLATES MAY contain zero or one [0..1] value with data type CD (CONF-GTR-58), where SHALL be selected from ValueSet DNA sequence variation change type STATIC a. GTR ClinicalGenomicStatementGeneticVariationDNAChange (self) SHALL satisfy: If (LOINC code for DNA sequence variation type), then self.value.code SHALL be drawn from the LOINC Value Set (DNA sequence variation type: ). (CONF-GTR-56) 6. Contains zero or more [0..*] methodcode 7. SHALL satisfy: GenomicAssociatedObservation shall be associated with a GenomicObservation within a ClinicalGenomicStatement. 8. GTR ClinicalGenomicStatementGeneticVariationDNAChange (self) SHALL satisfy: If self.code@code= (LOINC code for DNA sequence variation type), then self.value.code SHALL be drawn from the LOINC Value Set (DNA sequence variation type: ). (CONF-GTR-56) 9. SHALL satisfy: Either "DNA Change" observation or "Amino Acid Change" observation is required but both may be specified. <?xml version="1.0" encoding="utf-8"?> <observation xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd"> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <value xsi:type="cd" code=" "/> Figure 30: Genetic Variation Associated Observation DNA Change example Genetic Variation Associated Observation DNA Region Name [Observation: templateid ] The ClinicalGenomicStatementGeneticVariationDNAChange template is a sub-template of ClinicalGenomicStatement and is used to carry the DNA change of that genetic variation. 1. SHALL conform to Genomic Associated Observation template (templateid: ) 2. MAY contain exactly one [1..1] code (CONF-GTR-102)/@code=" " DNA Region Name (CodeSystem: LOINC) 3. MAY contain zero or one [0..1] value with data type ST 1. SHALL conform to Genomic Associated Observation template (templateid: ) 2. Contains exactly one with data type ActClassObservation 3. Contains exactly one with data type x_actmooddocumentobservation 4. MAY contain exactly one [1..1] code (CONF-GTR-102)/@code=" " DNA Region Name (CodeSystem: LOINC) 5. MAY contain zero or one [0..1] value with data type ST 6. Contains zero or more [0..*] methodcode 7. SHALL satisfy: GenomicAssociatedObservation shall be associated with a GenomicObservation within a ClinicalGenomicStatement. <?xml version="1.0" encoding="utf-8"?> Genetic Testing Report (GTR) Page 91

92 CLINICAL STATEMENT TEMPLATES 92 <observation xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd"> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <value xsi:type="st">text FOR VALUE</value> Figure 31: Genetic Variation Associated Observation DNA Region Name example Genetic Variation Associated Observation Zygosity [Observation: templateid ] The ClinicalGenomicStatementGeneticVariationDNAChange template is a sub-template of ClinicalGenomicStatement and is used to carry the DNA change of that genetic variation. 1. SHALL conform to Genomic Associated Observation template (templateid: ) 2. MAY contain exactly one [1..1] code/@code=" " Allelic State (CodeSystem: LOINC) (CONF-GTR-100) 3. MAY contain zero or one [0..1] value with data type CD, where MAY be selected from ValueSet Allelic State STATIC (CONF-GTR-101) a. GTR ClinicalGenomicStatementGeneticVariationDNAChange (self) SHALL satisfy: If self.code@code= (LOINC code for Allelic state), then self.value@code SHALL be drawn from the LOINC Value Set OID (Allelic State: ). (CONF-GTR-99) 4. If GenomicSourceClass.value@code = "Somatic" then this associated observation SHALL NOT be populated, else if GenomicSourceClass.value@code = "Germline" or "Prenatal", then this associated observation SHALL be populated. 1. SHALL conform to Genomic Associated Observation template (templateid: ) 2. Contains exactly one with data type ActClassObservation 3. Contains exactly one with data type x_actmooddocumentobservation 4. MAY contain exactly one [1..1] code/@code=" " Allelic State (CodeSystem: LOINC) (CONF-GTR-100) 5. MAY contain zero or one [0..1] value with data type CD, where MAY be selected from ValueSet Allelic State STATIC (CONF-GTR-101) a. GTR ClinicalGenomicStatementGeneticVariationDNAChange (self) SHALL satisfy: If self.code@code= (LOINC code for Allelic state), then self.value@code SHALL be drawn from the LOINC Value Set OID (Allelic State: ). (CONF-GTR-99) 6. Contains zero or more [0..*] methodcode 7. SHALL satisfy: GenomicAssociatedObservation shall be associated with a GenomicObservation within a ClinicalGenomicStatement. 8. GTR ClinicalGenomicStatementGeneticVariationDNAChange (self) SHALL satisfy: If self.code@code= (LOINC code for Allelic state), then self.value@code SHALL be drawn from the LOINC Value Set OID (Allelic State: ). (CONF-GTR-99) 9. If GenomicSourceClass.value@code = "Somatic" then this associated observation SHALL NOT be populated, else if GenomicSourceClass.value@code = "Germline" or "Prenatal", then this associated observation SHALL be populated. <?xml version="1.0" encoding="utf-8"?> Genetic Testing Report (GTR) Page 92

93 CLINICAL STATEMENT TEMPLATES 93 <observation xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd"> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> Figure 32: Genetic Variation Associated Observation Zygosity example Genomic Associated Observation Figure 33: Genomic Associated Observation example Genomic Observation Reference [Observation: templateid ] 1. Contains zero or more [0..*] id 2. SHALL satisfy: GenomicObservationReference shall not have any attribue except for id 1. Contains exactly one with data type ActClassObservation 2. Contains exactly one with data type x_actmooddocumentobservation 3. Contains zero or more [0..*] id 4. Contains exactly one [1..1] code with data type CD 5. SHALL satisfy: GenomicObservationReference shall not have any attribue except for id <?xml version="1.0" encoding="utf-8"?> <observation xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd"> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> Figure 34: Genomic Observation Reference example Genomic Observations Organizer [Act: templateid ] 1. SHALL contain exactly one (CodeSystem: HL7ActClass) 2. SHALL contain at least one [1..*] entryrelationship a. COMP b. Contains exactly one [1..1] Genomic Observation Reference (templateid: ) Genetic Testing Report (GTR) Page 93

94 CLINICAL STATEMENT TEMPLATES SHALL contain exactly one (CodeSystem: HL7ActClass) 2. Contains exactly one with data type x_documentactmood 3. Contains exactly one [1..1] code with data type CD 4. SHALL contain at least one [1..*] entryrelationship a. COMP b. Contains exactly one [1..1] Genomic Observation Reference (templateid: ) <?xml version="1.0" encoding="utf-8"?> <act xmlns:xsi=" xmlns="urn:hl7- org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd"> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <entryrelationship> <observation> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> </act> Figure 35: Genomic Observations Organizer example Genomic Source Class [Observation: templateid ] The GenomicSourceClass template represents the genomic class of the specimen being analyzed: Germline for inherited genome, somatic for cancer genome (e.g. DNA from tumor cells), and prenatal for fetal genome. 1. SHALL conform to Genomic Associated Observation template (templateid: ) 2. MAY contain exactly one [1..1] Genomic source class (CodeSystem: LOINC) (CONF-GTR-81) 3. MAY contain zero or one [0..1] value with data type CD (CONF-GTR-82), where SHALL be selected from ValueSet Genomic source class STATIC a. GTR GenomicSourceClass (self) SHALL satisfy: If self.code.code= (LOINC code for Genomic source class), then self.value.code SHALL be drawn from the LOINC answer list (CONF-GTR-80) 4. Contains zero or one [0..1] specimen a. Contains exactly one [1..1] CDA Specimen 1. SHALL conform to Genomic Associated Observation template (templateid: ) 2. Contains exactly one with data type ActClassObservation 3. Contains exactly one with data type x_actmooddocumentobservation Genetic Testing Report (GTR) Page 94

95 CLINICAL STATEMENT TEMPLATES MAY contain exactly one [1..1] Genomic source class (CodeSystem: LOINC) (CONF-GTR-81) 5. MAY contain zero or one [0..1] value with data type CD (CONF-GTR-82), where SHALL be selected from ValueSet Genomic source class STATIC a. GTR GenomicSourceClass (self) SHALL satisfy: If self.code.code= (LOINC code for Genomic source class), then self.value.code SHALL be drawn from the LOINC answer list (CONF-GTR-80) 6. Contains zero or more [0..*] methodcode 7. Contains zero or one [0..1] specimen a. Contains exactly one [1..1] CDA Specimen 8. SHALL satisfy: GenomicAssociatedObservation shall be associated with a GenomicObservation within a ClinicalGenomicStatement. 9. GTR GenomicSourceClass (self) SHALL satisfy: If self.code.code= (LOINC code for Genomic source class), then self.value.code SHALL be drawn from the LOINC answer list (CONF-GTR-80) <?xml version="1.0" encoding="utf-8"?> <observation xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd" classcode="obs" moodcode="evn"> <templateid root=" "/> <code code=" " codesystemname="loinc" displayname="genomic source class"/> <value xsi:type="cd" code="la6683-2" codesystemname="loinc" displayname="germline"/> <specimen> <templateid root=" "/> <specimenrole> <specimenplayingentity> <code code=" " codesystem=" " codesystemname="snomed-ct" displayname="peripheral blood specimen"/> </specimenplayingentity> </specimenrole> </specimen> Figure 36: Genomic Source Class example Indication Observation [Observation: templateid ] The IndicationObservation hangs off the genomic observation in the Clinical Genomic Statement template and represnet an indication to performing the genomic observation. It can also reside in the IndicationSection and then be referenced from a ClinicalGenomicStatement. 1. SHALL contain exactly one [1..1] code/@code="mthu008863" Indications description (CodeSystem: LOINC) (CONF-GTR-83) 2. Contains zero or one [0..1] value 1. Contains exactly one with data type ActClassObservation 2. Contains exactly one with data type x_actmooddocumentobservation 3. SHALL contain exactly one [1..1] code/@code="mthu008863" Indications description (CodeSystem: LOINC) (CONF-GTR-83) 4. Contains zero or one [0..1] value <?xml version="1.0" encoding="utf-8"?> Genetic Testing Report (GTR) Page 95

96 CLINICAL STATEMENT TEMPLATES 96 <observation xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd" classcode="obs" moodcode="evn"> <templateid root=" "/> <id root=" "/> <code code="mthu008863" codesystem=" " codesystemname="loinc" displayname="indications description"/> <effectivetime value="1950"/> <value xsi:type="cd" code="c26973" codesystemname="nci Thesaurus" displayname="sensory Hearing Loss"/> Figure 37: Indication Observation example Interpretive Phenotype [Observation: templateid ] The InterpretivePhenotypeObservation template is an abstract template for sub-templates that represent interpretations of specific types of genomic observation described in the various parts of the GTR. It can be associated with performers of the interpretations (note that these performers could be different than those performing the genetic observation itself). 1. MAY contain exactly one [1..1] code 2. MAY contain zero or one [0..1] value 1. Contains exactly one with data type ActClassObservation 2. Contains exactly one with data type x_actmooddocumentobservation 3. MAY contain exactly one [1..1] code 4. MAY contain zero or one [0..1] value <?xml version="1.0" encoding="utf-8"?> <observation xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd" classcode="obs" moodcode="def"> <templateid root=" "/> <code code=" " codesystemname="loinc" displayname="genetic disease analysis overall interpretation"/> <statuscode code="completed"/> <effectivetime value=" "/> <value xsi:type="cd" code="la9663-1" displayname="inconclusive"/> Figure 38: Interpretive Phenotype example Interpretive Phenotype Cytogenetics [Observation: templateid ] The InterpretivePhenotypeObservationCytogenetics is a sub-template of the InterpretivePhenotypeObservation abstract template, representing interpretations of Cytogenetic testing results. 1. SHALL conform to Interpretive Phenotype template (templateid: ) 2. MAY contain exactly one [1..1] code 3. MAY contain zero or one [0..1] value with data type CD 1. SHALL conform to Interpretive Phenotype template (templateid: ) 2. Contains exactly one with data type ActClassObservation Genetic Testing Report (GTR) Page 96

97 CLINICAL STATEMENT TEMPLATES Contains exactly one with data type x_actmooddocumentobservation 4. MAY contain exactly one [1..1] code 5. MAY contain zero or one [0..1] value with data type CD <?xml version="1.0" encoding="utf-8"?> <observation xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd"> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <value xsi:type="cd" code=" "/> Figure 39: Interpretive Phenotype Cytogenetics example Interpretive Phenotype Gene Expression [Observation: templateid ] The InterpretivePhenotypeObservationGeneExpression is a sub-template of the InterpretivePhenotypeObservation abstract template, representing interpretations of gene expression testing results. 1. SHALL conform to Interpretive Phenotype template (templateid: ) 2. MAY contain exactly one [1..1] code 3. Contains zero or one [0..1] value with data type CD 1. SHALL conform to Interpretive Phenotype template (templateid: ) 2. Contains exactly one with data type ActClassObservation 3. Contains exactly one with data type x_actmooddocumentobservation 4. MAY contain exactly one [1..1] code 5. Contains zero or one [0..1] value with data type CD <?xml version="1.0" encoding="utf-8"?> <observation xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd"> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <value xsi:type="cd" code=" "/> Figure 40: Interpretive Phenotype Gene Expression example Interpretive Phenotype Genetic Variation [Observation: templateid ] The InterpretivePhenotypeObservationGeneticVariation is a sub-template of the InterpretivePhenotypeObservation abstract template, representing interpretations of genetic variation testing results. 1. SHALL conform to Interpretive Phenotype template (templateid: ) Genetic Testing Report (GTR) Page 97

98 CLINICAL STATEMENT TEMPLATES MAY contain exactly one [1..1] Genetic disease sequence variation interpretation (CodeSystem: LOINC) (CONF-GTR-52) 3. MAY contain zero or one [0..1] value with data type CD (CONF-GTR-53), where SHALL be selected from ValueSet Genetic disease sequence variation interpretation STATIC a. GTR InterpretivePhenotypeObservationGeneticVariation (self) SHALL satisfy: If self.code.code= (LOINC code for Genetic disease sequence variation interpretation), then SHALL be drawn from the LOINC Value Set (Genetic disease sequence variation interpretation: ) (CONF-GTR-51) 1. SHALL conform to Interpretive Phenotype template (templateid: ) 2. Contains exactly one with data type ActClassObservation 3. Contains exactly one with data type x_actmooddocumentobservation 4. MAY contain exactly one [1..1] Genetic disease sequence variation interpretation (CodeSystem: LOINC) (CONF-GTR-52) 5. MAY contain zero or one [0..1] value with data type CD (CONF-GTR-53), where SHALL be selected from ValueSet Genetic disease sequence variation interpretation STATIC a. GTR InterpretivePhenotypeObservationGeneticVariation (self) SHALL satisfy: If self.code.code= (LOINC code for Genetic disease sequence variation interpretation), then SHALL be drawn from the LOINC Value Set (Genetic disease sequence variation interpretation: ) (CONF-GTR-51) 6. GTR InterpretivePhenotypeObservationGeneticVariation (self) SHALL satisfy: If self.code.code= (LOINC code for Genetic disease sequence variation interpretation), then SHALL be drawn from the LOINC Value Set (Genetic disease sequence variation interpretation: ) (CONF-GTR-51) <?xml version="1.0" encoding="utf-8"?> <observation xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd"> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <value xsi:type="cd" code=" "/> Figure 41: Interpretive Phenotype Genetic Variation example Interpretive Phenotype Pharmacogenomic [Observation: templateid ] The InterpretivePhenotypeObservationPharmacogenomic is a sub-template of the InterpretivePhenotypeObservation abstract template, representing interpretations of pharmacogenomic testing results. 1. SHALL conform to Interpretive Phenotype template (templateid: ) 2. MAY contain exactly one [1..1] code, where MAY be selected from (CONF-GTR-49) 3. MAY contain zero or one [0..1] value with data type CD (CONF-GTR-50) 1. SHALL conform to Interpretive Phenotype template (templateid: ) 2. Contains exactly one with data type ActClassObservation 3. Contains exactly one with data type x_actmooddocumentobservation Genetic Testing Report (GTR) Page 98

99 CLINICAL STATEMENT TEMPLATES MAY contain exactly one [1..1] code, where MAY be selected from (CONF-GTR-49) 5. MAY contain zero or one [0..1] value with data type CD (CONF-GTR-50) <?xml version="1.0" encoding="utf-8"?> <observation xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd"> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <value xsi:type="cd" code=" "/> Figure 42: Interpretive Phenotype Pharmacogenomic example Interpretive Phenotype Pharmacogenomic Drug Efficacy [Observation: templateid ] The InterpretivePhenotypeObservationPharmacogenomicDrugEfficacy is a sub-template of the InterpretivePhenotypeObservationPharmacogenomic template, representing interpretations of drug efficacy testing results. 1. SHALL conform to Interpretive Phenotype Pharmacogenomic template (templateid: ) 2. MAY contain exactly one [1..1] code/@code=" " Drug efficacy sequence variation interpretation (CodeSystem: LOINC) (CONF-GTR-63) 3. MAY contain zero or one [0..1] value with data type CD (CONF-GTR-64), where SHALL be selected from ValueSet Drug Efficacy Sequence Variation Interpretation STATIC a. GTR InterpretivePhenotypeObservationPharmacogenomicDrugEfficacy (self) SHALL satisfy: If self.code@code= (LOINC code for Drug efficacy sequence variation interpretation), then self.value@code SHALL be drawn from the LOINC Value Set (Drug efficacy sequence variation interpretation: ). (CONF-GTR-62) 1. SHALL conform to Interpretive Phenotype template (templateid: ) 2. SHALL conform to Interpretive Phenotype Pharmacogenomic template (templateid: ) 3. Contains exactly one with data type ActClassObservation 4. Contains exactly one with data type x_actmooddocumentobservation 5. MAY contain exactly one [1..1] code/@code=" " Drug efficacy sequence variation interpretation (CodeSystem: LOINC) (CONF-GTR-63) 6. MAY contain zero or one [0..1] value with data type CD (CONF-GTR-64), where SHALL be selected from ValueSet Drug Efficacy Sequence Variation Interpretation STATIC a. GTR InterpretivePhenotypeObservationPharmacogenomicDrugEfficacy (self) SHALL satisfy: If self.code@code= (LOINC code for Drug efficacy sequence variation interpretation), then self.value@code SHALL be drawn from the LOINC Value Set (Drug efficacy sequence variation interpretation: ). (CONF-GTR-62) 7. GTR InterpretivePhenotypeObservationPharmacogenomicDrugEfficacy (self) SHALL satisfy: If self.code@code= (LOINC code for Drug efficacy sequence variation interpretation), then self.value@code SHALL be drawn from the LOINC Value Set (Drug efficacy sequence variation interpretation: ). (CONF-GTR-62) Genetic Testing Report (GTR) Page 99

100 CLINICAL STATEMENT TEMPLATES 100 <?xml version="1.0" encoding="utf-8"?> <observation xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd"> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <value xsi:type="cd" code=" "/> Figure 43: Interpretive Phenotype Pharmacogenomic Drug Efficacy example Interpretive Phenotype Pharmacogenomic Drug Metabolism [Observation: templateid ] The InterpretivePhenotypeObservationPharmacogenomicDrugMetabolism is a sub-template of the InterpretivePhenotypeObservationPharmacogenomic template, representing interpretations of drug metabolism testing results. 1. SHALL conform to Interpretive Phenotype Pharmacogenomic template (templateid: ) 2. MAY contain exactly one [1..1] code/@code=" " Drug metabolism sequence variation interpretation (CodeSystem: LOINC) (CONF-GTR-66) 3. MAY contain zero or one [0..1] value with data type CD (CONF-GTR-67), where SHALL be selected from ValueSet Drug metabolism sequence variation interpretation STATIC a. GTR InterpretivePhenotypeObservationPharmacogenomicDrugMetabolism (self) SHALL satisfy: If self.code@code= (LOINC code for Drug metabolism sequence variation interpretation), then self.value@code SHALL be drawn from the LOINC Value Set (Drug metabolism sequence variation interpretation: ). (CONF-GTR-65) 1. SHALL conform to Interpretive Phenotype template (templateid: ) 2. SHALL conform to Interpretive Phenotype Pharmacogenomic template (templateid: ) 3. Contains exactly one with data type ActClassObservation 4. Contains exactly one with data type x_actmooddocumentobservation 5. MAY contain exactly one [1..1] code/@code=" " Drug metabolism sequence variation interpretation (CodeSystem: LOINC) (CONF-GTR-66) 6. MAY contain zero or one [0..1] value with data type CD (CONF-GTR-67), where SHALL be selected from ValueSet Drug metabolism sequence variation interpretation STATIC a. GTR InterpretivePhenotypeObservationPharmacogenomicDrugMetabolism (self) SHALL satisfy: If self.code@code= (LOINC code for Drug metabolism sequence variation interpretation), then self.value@code SHALL be drawn from the LOINC Value Set (Drug metabolism sequence variation interpretation: ). (CONF-GTR-65) 7. GTR InterpretivePhenotypeObservationPharmacogenomicDrugMetabolism (self) SHALL satisfy: If self.code@code= (LOINC code for Drug metabolism sequence variation interpretation), then self.value@code SHALL be drawn from the LOINC Value Set (Drug metabolism sequence variation interpretation: ). (CONF-GTR-65) <?xml version="1.0" encoding="utf-8"?> Genetic Testing Report (GTR) Page 100

101 CLINICAL STATEMENT TEMPLATES 101 <observation xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd"> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <value xsi:type="cd" code=" "/> Figure 44: Interpretive Phenotype Pharmacogenomic Drug Metabolism example Overall Interpretive Phenotype Chromosome Analysis [Observation: templateid ] 1. SHALL conform to Interpretive Phenotype template (templateid: ) 2. MAY contain exactly one [1..1] Chromosome analysis overall interpretation in Blood or Tissue Qualitative by Molecular genetics method (CodeSystem: LOINC) 3. MAY contain zero or one [0..1] value with data type CD, where SHALL be selected from ValueSet Chromosome analysis overall interpretation STATIC a. GTR OverallInterpretivePhenotypeObservationCytogenetics (self) SHALL satisfy: If (LOINC code for Chromosome analysis overall interpretation in Blood or Tissue Qualitative by Molecular), then SHALL be drawn from the LOINC Value Set (Chromosome analysis overall interpretation in Blood or Tissue Qualitative by Molecular: ). 1. SHALL conform to Interpretive Phenotype template (templateid: ) 2. Contains exactly one with data type ActClassObservation 3. Contains exactly one with data type x_actmooddocumentobservation 4. MAY contain exactly one [1..1] Chromosome analysis overall interpretation in Blood or Tissue Qualitative by Molecular genetics method (CodeSystem: LOINC) 5. MAY contain zero or one [0..1] value with data type CD, where SHALL be selected from ValueSet Chromosome analysis overall interpretation STATIC a. GTR OverallInterpretivePhenotypeObservationCytogenetics (self) SHALL satisfy: If (LOINC code for Chromosome analysis overall interpretation in Blood or Tissue Qualitative by Molecular), then SHALL be drawn from the LOINC Value Set (Chromosome analysis overall interpretation in Blood or Tissue Qualitative by Molecular: ). 6. GTR OverallInterpretivePhenotypeObservationCytogenetics (self) SHALL satisfy: If (LOINC code for Chromosome analysis overall interpretation in Blood or Tissue Qualitative by Molecular), then SHALL be drawn from the LOINC Value Set (Chromosome analysis overall interpretation in Blood or Tissue Qualitative by Molecular: ). <?xml version="1.0" encoding="utf-8"?> <observation xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd"> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> Genetic Testing Report (GTR) Page 101

102 CLINICAL STATEMENT TEMPLATES 102 <low value="2012"/> <high value="2012"/> </effectivetime> <value xsi:type="cd" code=" "/> Figure 45: Overall Interpretive Phenotype Chromosome Analysis example Overall Interpretive Phenotype Genetic Disease [Observation: templateid ] The OverallInterpretivePhenotypeObservationGeneticDisease template extends InterpretivePhenotypeObserbation and describes the overall interpretation of the genetic variation testing performed. 1. SHALL conform to Interpretive Phenotype template (templateid: ) 2. MAY contain zero or one [0..1] Genetic Disease Analysis Overall Interpretation (CodeSystem: LOINC) (CONF-GTR-23) 3. MAY contain zero or one [0..1] value with data type CD, where MAY be selected from ValueSet Genetic disease analysis overall interpretation STATIC (CONF-GTR-24) a. GTR OverallInterpretivePhenotypeObservationGeneticDisease (self) SHALL satisfy: If (LOINC code forgenetic Disease Analysis Overall Interpretation), then SHALL be drawn from the LOINC Value Set (Genetic Disease Analysis Overall Interpretation: ). (CONF-GTR-22) 1. SHALL conform to Interpretive Phenotype template (templateid: ) 2. Contains exactly one with data type ActClassObservation 3. Contains exactly one with data type x_actmooddocumentobservation 4. MAY contain zero or one [0..1] Genetic Disease Analysis Overall Interpretation (CodeSystem: LOINC) (CONF-GTR-23) 5. MAY contain zero or one [0..1] value with data type CD, where MAY be selected from ValueSet Genetic disease analysis overall interpretation STATIC (CONF-GTR-24) a. GTR OverallInterpretivePhenotypeObservationGeneticDisease (self) SHALL satisfy: If (LOINC code forgenetic Disease Analysis Overall Interpretation), then SHALL be drawn from the LOINC Value Set (Genetic Disease Analysis Overall Interpretation: ). (CONF-GTR-22) 6. GTR OverallInterpretivePhenotypeObservationGeneticDisease (self) SHALL satisfy: If (LOINC code forgenetic Disease Analysis Overall Interpretation), then SHALL be drawn from the LOINC Value Set (Genetic Disease Analysis Overall Interpretation: ). (CONF-GTR-22) <?xml version="1.0" encoding="utf-8"?> <observation xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd" classcode="obs" moodcode="def"> <templateid root=" "/> <code code=" " codesystemname="loinc" displayname="genetic disease analysis overall interpretation"/> <statuscode code="completed"/> <effectivetime value=" "/> <value xsi:type="cd" code="la9663-1" displayname="inconclusive"/> Figure 46: Overall Interpretive Phenotype Genetic Disease example Genetic Testing Report (GTR) Page 102

103 CLINICAL STATEMENT TEMPLATES 103 Overall Interpretive Phenotype Genetic Disease Carrier [Observation: templateid ] The OverallInterpretivePhenotypeObservationGeneticDiseaseCarrier template extends InterpretivePhenotypeObserbation and describes the overall interpretation of the genetic disease carrier testing performed. 1. SHALL conform to Interpretive Phenotype template (templateid: ) 2. MAY contain zero or one [0..1] Genetic disease analysis overall carrier interpretation (CodeSystem: LOINC) (CONF-GTR-78) 3. MAY contain zero or one [0..1] value with data type CD (CONF-GTR-79), where SHALL be selected from ValueSet Genetic disease analysis overall carrier interpretation STATIC a. GTR OverallInterpretivePhenotypeObservationGeneticDiseaseCarrier (self) SHALL satisfy: If (LOINC code for Genetic disease analysis overall carrier interpretation), then SHALL be drawn from the LOINC Value Set (Genetic disease analysis overall carrier interpretation: ). (CONF-GTR-77) 1. SHALL conform to Interpretive Phenotype template (templateid: ) 2. Contains exactly one with data type ActClassObservation 3. Contains exactly one with data type x_actmooddocumentobservation 4. MAY contain zero or one [0..1] Genetic disease analysis overall carrier interpretation (CodeSystem: LOINC) (CONF-GTR-78) 5. MAY contain zero or one [0..1] value with data type CD (CONF-GTR-79), where SHALL be selected from ValueSet Genetic disease analysis overall carrier interpretation STATIC a. GTR OverallInterpretivePhenotypeObservationGeneticDiseaseCarrier (self) SHALL satisfy: If (LOINC code for Genetic disease analysis overall carrier interpretation), then SHALL be drawn from the LOINC Value Set (Genetic disease analysis overall carrier interpretation: ). (CONF-GTR-77) 6. GTR OverallInterpretivePhenotypeObservationGeneticDiseaseCarrier (self) SHALL satisfy: If (LOINC code for Genetic disease analysis overall carrier interpretation), then SHALL be drawn from the LOINC Value Set (Genetic disease analysis overall carrier interpretation: ). (CONF-GTR-77) <?xml version="1.0" encoding="utf-8"?> <observation xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd"> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <value xsi:type="cd" code=" "/> Figure 47: Overall Interpretive Phenotype Genetic Disease Carrier example Genetic Testing Report (GTR) Page 103

104 CLINICAL STATEMENT TEMPLATES 104 Overall Interpretive Phenotype Pharmacogenomic Drug Efficacy [Observation: templateid ] The OverallInterpretivePhenotypeObservationPharmacogenomicDrugEfficacy template extends InterpretivePhenotypeObserbation and describes the overall interpretation of the pharmacogenomic drug efficacy testing performed. 1. SHALL conform to Interpretive Phenotype Pharmacogenomic template (templateid: ) 2. MAY contain exactly one [1..1] Drug efficacy analysis overall interpretation (CONF-GTR-72) 3. MAY contain zero or one [0..1] value with data type CD (CONF-GTR-73), where SHALL be selected from ValueSet Drug efficacy analysis overall interpretation STATIC a. GTR OverallInterpretivePhenotypeObservationPharmacogenomicDrugEfficacy (self) SHALL satisfy: If (LOINC code for Drug efficacy analysis overall interpretation), then SHALL be drawn from the LOINC Value Set (Drug efficacy analysis overall interpretation: ). (CONF-GTR-71) 1. SHALL conform to Interpretive Phenotype template (templateid: ) 2. SHALL conform to Interpretive Phenotype Pharmacogenomic template (templateid: ) 3. Contains exactly one with data type ActClassObservation 4. Contains exactly one with data type x_actmooddocumentobservation 5. MAY contain exactly one [1..1] Drug efficacy analysis overall interpretation (CONF-GTR-72) 6. MAY contain zero or one [0..1] value with data type CD (CONF-GTR-73), where SHALL be selected from ValueSet Drug efficacy analysis overall interpretation STATIC a. GTR OverallInterpretivePhenotypeObservationPharmacogenomicDrugEfficacy (self) SHALL satisfy: If (LOINC code for Drug efficacy analysis overall interpretation), then SHALL be drawn from the LOINC Value Set (Drug efficacy analysis overall interpretation: ). (CONF-GTR-71) 7. GTR OverallInterpretivePhenotypeObservationPharmacogenomicDrugEfficacy (self) SHALL satisfy: If (LOINC code for Drug efficacy analysis overall interpretation), then SHALL be drawn from the LOINC Value Set (Drug efficacy analysis overall interpretation: ). (CONF-GTR-71) <?xml version="1.0" encoding="utf-8"?> <observation xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd"> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <value xsi:type="cd" code=" "/> Figure 48: Overall Interpretive Phenotype Pharmacogenomic Drug Efficacy example Genetic Testing Report (GTR) Page 104

105 CLINICAL STATEMENT TEMPLATES 105 Overall Interpretive Phenotype Pharmacogenomic Drug Metabolism [Observation: templateid ] The OverallInterpretivePhenotypeObservationPharmacogenomicDrugMetabolism template extends InterpretivePhenotypeObserbation and describes the overall interpretation of the pharmacogenomic drug Metabolism testing performed. 1. SHALL conform to Interpretive Phenotype Pharmacogenomic template (templateid: ) 2. MAY contain exactly one [1..1] Drug metabolism analysis overall interpretation (CodeSystem: LOINC) (CONF-GTR-75) 3. MAY contain zero or one [0..1] value with data type CD (CONF-GTR-76), where SHALL be selected from ValueSet Drug metabolism analysis overall interpretation STATIC a. GTR OverallInterpretivePhenotypeObservationPharmacogenomicDrugMetabolism (self) SHALL satisfy: If (LOINC code for Drug metabolism analysis overall interpretation), then SHALL be drawn from the LOINC Value Set (Drug metabolism analysis overall interpretation: ). (CONF-GTR-74) 1. SHALL conform to Interpretive Phenotype template (templateid: ) 2. SHALL conform to Interpretive Phenotype Pharmacogenomic template (templateid: ) 3. Contains exactly one with data type ActClassObservation 4. Contains exactly one with data type x_actmooddocumentobservation 5. MAY contain exactly one [1..1] Drug metabolism analysis overall interpretation (CodeSystem: LOINC) (CONF-GTR-75) 6. MAY contain zero or one [0..1] value with data type CD (CONF-GTR-76), where SHALL be selected from ValueSet Drug metabolism analysis overall interpretation STATIC a. GTR OverallInterpretivePhenotypeObservationPharmacogenomicDrugMetabolism (self) SHALL satisfy: If (LOINC code for Drug metabolism analysis overall interpretation), then SHALL be drawn from the LOINC Value Set (Drug metabolism analysis overall interpretation: ). (CONF-GTR-74) 7. GTR OverallInterpretivePhenotypeObservationPharmacogenomicDrugMetabolism (self) SHALL satisfy: If (LOINC code for Drug metabolism analysis overall interpretation), then SHALL be drawn from the LOINC Value Set (Drug metabolism analysis overall interpretation: ). (CONF-GTR-74) <?xml version="1.0" encoding="utf-8"?> <observation xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd"> <id root="mdht" extension=" "/> <code code=" "/> <effectivetime> <low value="2012"/> <high value="2012"/> </effectivetime> <value xsi:type="cd" code=" "/> Figure 49: Overall Interpretive Phenotype Pharmacogenomic Drug Metabolism example Genetic Testing Report (GTR) Page 105

106 CLINICAL STATEMENT TEMPLATES 106 Test Performed Observation [Observation: templateid ] The TestPerformedObservation describes one of the tests performed whose results are reported in the GTR. It can be used by the TestsPerformedSection to describe each test in a structured format. 1. SHOULD contain zero or one [0..1] code (CONF-GTR-87) The code attribute should identify the type (or class) of genetic testing at stake, preferably drawn from a published classification / terminology, e.g., "Hereditary Hearing Loss and Deafness" where the value attribute can hold a code representing the test titled "Connexin 26 Full Gene Test", preferably drawn from a published catalog. 2. SHALL contain exactly one [1..1] value with data type CD (CONF-GTR-88) The value attribute should be aligned with the semantics of the code assigned to the code attribute, e.g., if code = "Hereditary Hearing Loss and Deafness" then the value attribute can hold a code representing the test titled "Connexin 26 Full Gene Test", preferably drawn from a published catalog. 3. SHOULD contain zero or one [0..1] methodcode (CONF-GTR-89) The methodcode can provide more information on the test identified through the value and optionally the code attributes of this observation. The code assigned to methodcode should preferably be drawn from a standard terminology for genetic testing methods. 1. Contains exactly one with data type ActClassObservation 2. Contains exactly one with data type x_actmooddocumentobservation 3. SHOULD contain zero or one [0..1] code (CONF-GTR-87) The code attribute should identify the type (or class) of genetic testing at stake, preferably drawn from a published classification / terminology, e.g., "Hereditary Hearing Loss and Deafness" where the value attribute can hold a code representing the test titled "Connexin 26 Full Gene Test", preferably drawn from a published catalog. 4. SHALL contain exactly one [1..1] value with data type CD (CONF-GTR-88) The value attribute should be aligned with the semantics of the code assigned to the code attribute, e.g., if code = "Hereditary Hearing Loss and Deafness" then the value attribute can hold a code representing the test titled "Connexin 26 Full Gene Test", preferably drawn from a published catalog. 5. SHOULD contain zero or one [0..1] methodcode (CONF-GTR-89) The methodcode can provide more information on the test identified through the value and optionally the code attributes of this observation. The code assigned to methodcode should preferably be drawn from a standard terminology for genetic testing methods. <?xml version="1.0" encoding="utf-8"?> <observation xmlns:xsi=" xmlns="urn:hl7-org:v3" xsi:schemalocation="urn:hl7-org:v3 CDA.xsd" classcode="obs" moodcode="evn"> <templateid root=" "/> <code displayname="test Performed"/> <statuscode code="completed"/> <effectivetime value=" "/> <value xsi:type="cd" code="cx26full" codesystem=" " codesystemname="loinc" displayname="connexin 26 Full Gene Test"> <originaltext> <reference value="#a1"/> </originaltext> </value> <entryrelationship typecode="rson"> <observation classcode="cond" moodcode="evn"> <id root=" "/> <code/> Genetic Testing Report (GTR) Page 106

107 CLINICAL STATEMENT TEMPLATES 107 Figure 50: Test Performed Observation example Genetic Testing Report (GTR) Page 107

108 CLINICAL STATEMENT TEMPLATES 108 Genetic Testing Report (GTR) Page 108

109 Chapter 5 OTHER CLASSES This section of the Implementation Guide describes other classes that are not CDA Clinical Documents, Sections, or Clinical Statements.

110 OTHER CLASSES 110 Genetic Testing Report (GTR) Page 110

111 Chapter 6 VALUE SETS Topics: Allelic State Amino acid change type Chromosome analysis overall interpretation DNA sequence variation change type Drug efficacy analysis overall interpretation Drug Efficacy Sequence Variation Interpretation Drug metabolism analysis overall interpretation Drug metabolism sequence variation interpretation Genetic disease analysis overall carrier interpretation Genetic disease analysis overall interpretation Genetic disease sequence variation interpretation Genomic source class ISCN band level The following tables summarize the value sets used in this Implementation Guide.

112 VALUE SETS 112 Allelic State Value Set Allelic State Code System LOINC Code Code System Print Name LA LOINC Homozygous LA LOINC Heterozygous LA LOINC Heteroplasmic LA LOINC Homoplasmic LA LOINC Hemizygous Amino acid change type Value Set Amino acid change type Code System LOINC Code Code System Print Name LA LOINC Wild type LA LOINC Deletion LA LOINC Duplication LA LOINC Frameshift LA LOINC Initiating Methionine LA LOINC Insertion LA LOINC Insertion and Deletion LA LOINC Missense LA LOINC Nonsense LA LOINC Silent LA LOINC Stop Codon Mutation Chromosome analysis overall interpretation Value Set Chromosome analysis overall interpretation Code System LOINC Code Code System Print Name Normal LOINC LA Abnormal LOINC LA Genetic Testing Report (GTR) Page 112

113 VALUE SETS 113 Code Code System Print Name Clinical significance unkown LOINC LA DNA sequence variation change type Value Set DNA sequence variation change type Code System LOINC Code Code System Print Name LA LOINC Wild type LA LOINC Deletion LA LOINC Duplication LA LOINC Insertion LA LOINC Insertion/Deletion LA LOINC Inversion LA LOINC Substitution Drug efficacy analysis overall interpretation Value Set Drug efficacy analysis overall interpretation Code System LOINC Code Code System Print Name LA LOINC Responsive LA LOINC Resistant LA LOINC Negative LA LOINC Inconclusive LA LOINC Failure Drug Efficacy Sequence Variation Interpretation Value Set Drug Efficacy Sequence Variation Interpretation Code System LOINC Code Code System Print Name LA LOINC Resistant LA LOINC Responsive LA LOINC Presumed resistant Genetic Testing Report (GTR) Page 113

114 VALUE SETS 114 Code Code System Print Name LA LOINC Presumed responsive LA LOINC Unknown Significance LA LOINC Benign LA LOINC Presumed Benign LA LOINC Presumed non-responsive Drug metabolism analysis overall interpretation Value Set Drug metabolism analysis overall interpretation Code Code System Print Name LA LOINC Ultrarapid metabolizer LA LOINC Extensive metabolizer LA LOINC Intermediate metabolizer LA LOINC Poor metabolizer LA LOINC Inconclusive Drug metabolism sequence variation interpretation Value Set Drug metabolism sequence variation interpretation Code Code System Print Name LA LOINC Ultrarapid metabolizer LA LOINC Extensive metabolizer LA LOINC Intermediate metabolizer LA LOINC Poor metabolizer LA Unknown Significance Genetic disease analysis overall carrier interpretation Value Set Genetic disease analysis overall carrier interpretation Code System LOINC Code Code System Print Name LA LOINC Carrier LA LOINC Negative LA LOINC Inconclusive LA LOINC Failure Genetic Testing Report (GTR) Page 114

115 VALUE SETS 115 Genetic disease analysis overall interpretation Value Set Genetic disease analysis overall interpretation Code System LOINC Definition Defines concept codes for LOINC answer list. Code Code System Print Name LA LOINC Positive LA LOINC Negative LA LOINC Inconclusive LA LOINC Failure Genetic disease sequence variation interpretation Value Set Genetic disease sequence variation interpretation Code System LOINC Code Code System Print Name LA LOINC Pathogenic LA LOINC Presumed pathogenic LA LOINC Unknown significance LA LOINC Benign LA LOINC Presumed benign Genomic source class Value Set Genomic source class Code System LOINC Definition The genomic class of the specimen being analyzed: Germline for inherited genome, somatic for cancer genome, and prenatal for fetal genome. Code Code System Print Name LA LOINC Germline LA LOINC Somatic LA LOINC Prenatal ISCN band level Value Set ISCN band level Genetic Testing Report (GTR) Page 115

116 VALUE SETS 116 Code System LOINC Code Code System Print Name LA LOINC 400 LA LOINC 425 LA LOINC 450 LA LOINC 500 LA LOINC 550 LA LOINC 575 LA LOINC 600 LA LOINC 650 LA LOINC 800 LA LOINC 850 Genetic Testing Report (GTR) Page 116

117 REFERENCES HL7 Implementation Guide: CDA Release 2 Continuity of Care Document (CCD) A CDA implementation of ASTM E Standard Specification for Continuity of Care Record (CCR) April 01, 2007 available through HL7. Dolin RH, Alschuler L, Boyer S, Beebe C, Behlen FM, Biron PV, Shabo A, (Editors). HL7 Clinical Document Architecture, Release 2.0. ANSI-approved HL7 Standard; May Ann Arbor, Mich.: Health Level Seven, Inc. Available through HL7 or if an HL7 member with the following link: CDA Release 2 Normative Web Edition. LOINC : Logical Observation Identifiers Names and Codes, Regenstrief Institute. SNOMED CT : SNOMED Clinical Terms SNOMED International Organization. Extensible Markup Language, Dolin RH, Alschuler L, Boyer S, Beebe C, Behlen FM, Biron PV, Shabo A., HL7 Clinical Document Architecture, Release 2. J Am Med Inform Assoc. 2006;13: Available at: reprint/13/1/30. HL7 Clinical Genomics v3 specification. Available through HL7 HL7 Clinical Genomics v2 specification for genetic testing results message. Available through HL7

118 REFERENCES 118 Genetic Testing Report (GTR) Page 118