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10.10 Genomics Implementation Guidance

Clinical Genomics Work Group

Maturity Level: 1

Standards Status: Trial Use

Table of Contents

1. Background
2. Overview
3. MolecularSequence Resource
4. Relationship among MolecularSequence resource and profiles
5. HL7 Domain Analysis Model Use Cases
6. Other Genomics Use Cases
7. Clinical Genomics Apps

Trial-Use Note:

The material on this page is currently undergoing work to be refactored in a future release as further analysis is done, for example as part of the Genomics Reporting Implementation Guide .

10.10 Background

Rapid advances in sequencing technologies, clinical genetics tests for whole genome and exome sequencing are allowing sophisticated genetics testing to be used by providers and patients in clinical decisions. Results from such tests are used to identify distinct genetic variants that may contribute to syndromes, conditions and/or predictive responses to treatments. The implementation of precision medicine will depend upon having such data to diagnose patients, choose medications, and predict the course of disease and care, but will require standards and effective user interfaces.

A current technical challenge exists in interoperability, the ability to access and share clinical and genetics data. The challenges of interoperability includes collection, coding, and retrieval to scale. An individual's genetic data set is large, complex and requires curation. Unfortunately, incompatible systems and nomenclatures are already in use. A standards-based ontology that could be adopted to integrate both genetic data and clinical information systems will be crucial to accelerating the integration of precision medicine and to make sense of genetic testing results in a complete clinical context.

One approach for collecting, coding, and retrieving genetics data comes from the Global Alliance for Genomics and Health (GA4GH). The GA4GH organization has built and is refining an API and data model for the exchange of full sequence genomic information across multiple research organizations and platforms. The GA4GH focuses on the needs of researchers.

A second approach is evolving from HL7 through FHIR. FHIR is attractive because it is relatively easy to implement because it is comprised of a set of modular components called resources, which can be easily and incrementally assembled into working systems. The clinical requirements for genetics data is, relative to genomics research needs, utilitarian and reductive because it is about distilling and extracting particular genetics data produced by ever more sophisticated testing for use at the point-of-care. This has made FHIR a very functional framework to initiate an interoperable clinical genetics data standardization to which multiple stakeholders have contributed to this guide.

FHIR DSTU2 introduced a standard genetics profile that applies to the FHIR Observation resource. Using this profile, Observation payloads can return genetic testing results in a standardized manner. In STU3, a new resource to be called MolecularSequence was created allowing for increased granularity and less ambiguity.

In addition to the MolecularSequence, a new FHIR Implementation Guide Genomics Reporting Implementation Guide is being developed. At present, this implementation guide focuses solely on data structures - what data should be/might be present and how it should be organized. It does not address workflows around how reports are requested, created, approved, routed, delivered, amended, etc. The implementation guide is also paradigm-independent - the data structures presented here could be used in RESTful, messaging, documents or other mechanisms.

10.10 MolecularSequence Overview

This resource will be used to hold clinically relevant sequence data in a manner that is both efficient and versatile integrating new and as yet undefined types of genomic and other -omics data that will soon be commonly entered into health records for clinical use. MolecularSequence will be leveraged by other FHIR resources, including Observation. This is consistent with how all FHIR resources are designed and used.

With this resource and profiles found in the Genomics Reporting Implementation Guide , FHIR can support a large set of clinical use cases (see Section 9, 10 , and 11) and is thus positioned to address all emergent -omics use cases, including Next-Generation Sequencing (NGS). These tools are simple to implement, will optimize payload sizes, and help developers avoid redundant retrieval of data.

The September 2014 Informative Ballot (“HL7 Clinical Genomics, Domain Analysis Model: Clinical Sequencing Release 1”) provided guiding use cases, which initially informed development of the initial Standard Genetics profile that is found in FHIR DSTU2. The same use cases also led to a second Project to develop a MolecularSequence resource (“Develop FHIR sequence resource for Clinical Genomics”). A preliminary effort to address these issues has been explored and published in context of the Substitutable Medical Applications and Reusable Technologies (SMART) Platforms Project and described in an article (“SMART on FHIR Genomics: Facilitating standardized clinico-genomic apps ”).

10.10 MolecularSequence Resource

10.10.1 Structure Diagram

Name	Flags	Card.	Type	Description & Constraints
MolecularSequence	TU		DomainResource	Information about a biological sequence + Rule: Only 0 and 1 are valid for coordinateSystem Elements defined in Ancestors: id, meta, implicitRules, language, text, contained, extension, modifierExtension
identifier	Σ	0..*	Identifier	Unique ID for this particular sequence. This is a FHIR-defined id
type	Σ	0..1	code	aa | dna | rna sequenceType (Required)
coordinateSystem	Σ	1..1	integer	Base number of coordinate system (0 for 0-based numbering or coordinates, inclusive start, exclusive end, 1 for 1-based numbering, inclusive start, inclusive end)
patient	Σ	0..1	Reference(Patient)	Who and/or what this is about
specimen	Σ	0..1	Reference(Specimen)	Specimen used for sequencing
device	Σ	0..1	Reference(Device)	The method for sequencing
performer	Σ	0..1	Reference(Organization)	Who should be responsible for test result
quantity	Σ	0..1	Quantity	The number of copies of the sequence of interest. (RNASeq)
referenceSeq	ΣI	0..1	BackboneElement	A sequence used as reference + Rule: GenomeBuild and chromosome must be both contained if either one of them is contained + Rule: Have and only have one of the following elements in referenceSeq : 1. genomeBuild ; 2 referenceSeqId; 3. referenceSeqPointer; 4. referenceSeqString;
chromosome	Σ	0..1	CodeableConcept	Chromosome containing genetic finding chromosome-human (Example)
genomeBuild	Σ	0..1	string	The Genome Build used for reference, following GRCh build versions e.g. 'GRCh 37'
orientation	Σ	0..1	code	sense | antisense orientationType (Required)
referenceSeqId	Σ	0..1	CodeableConcept	Reference identifier ENSEMBL (Example)
referenceSeqPointer	Σ	0..1	Reference(MolecularSequence)	A pointer to another MolecularSequence entity as reference sequence
referenceSeqString	Σ	0..1	string	A string to represent reference sequence
strand	Σ	0..1	code	watson | crick strandType (Required)
windowStart	Σ	0..1	integer	Start position of the window on the reference sequence
windowEnd	Σ	0..1	integer	End position of the window on the reference sequence
variant	Σ	0..*	BackboneElement	Variant in sequence
start	Σ	0..1	integer	Start position of the variant on the reference sequence
end	Σ	0..1	integer	End position of the variant on the reference sequence
observedAllele	Σ	0..1	string	Allele that was observed
referenceAllele	Σ	0..1	string	Allele in the reference sequence
cigar	Σ	0..1	string	Extended CIGAR string for aligning the sequence with reference bases
variantPointer	Σ	0..1	Reference(Observation)	Pointer to observed variant information
observedSeq	Σ	0..1	string	Sequence that was observed
quality	Σ	0..*	BackboneElement	An set of value as quality of sequence
type	Σ	1..1	code	indel | snp | unknown qualityType (Required)
standardSequence	Σ	0..1	CodeableConcept	Standard sequence for comparison FDA-StandardSequence (Example)
start	Σ	0..1	integer	Start position of the sequence
end	Σ	0..1	integer	End position of the sequence
score	Σ	0..1	Quantity	Quality score for the comparison
method	Σ	0..1	CodeableConcept	Method to get quality FDA-Method (Example)
truthTP	Σ	0..1	decimal	True positives from the perspective of the truth data
queryTP	Σ	0..1	decimal	True positives from the perspective of the query data
truthFN	Σ	0..1	decimal	False negatives
queryFP	Σ	0..1	decimal	False positives
gtFP	Σ	0..1	decimal	False positives where the non-REF alleles in the Truth and Query Call Sets match
precision	Σ	0..1	decimal	Precision of comparison
recall	Σ	0..1	decimal	Recall of comparison
fScore	Σ	0..1	decimal	F-score
roc	Σ	0..1	BackboneElement	Receiver Operator Characteristic (ROC) Curve
score	Σ	0..*	integer	Genotype quality score
numTP	Σ	0..*	integer	Roc score true positive numbers
numFP	Σ	0..*	integer	Roc score false positive numbers
numFN	Σ	0..*	integer	Roc score false negative numbers
precision	Σ	0..*	decimal	Precision of the GQ score
sensitivity	Σ	0..*	decimal	Sensitivity of the GQ score
fMeasure	Σ	0..*	decimal	FScore of the GQ score
readCoverage	Σ	0..1	integer	Average number of reads representing a given nucleotide in the reconstructed sequence
repository	Σ	0..*	BackboneElement	External repository which contains detailed report related with observedSeq in this resource
type	Σ	1..1	code	directlink | openapi | login | oauth | other repositoryType (Required)
url	Σ	0..1	uri	URI of the repository
name	Σ	0..1	string	Repository's name
datasetId	Σ	0..1	string	Id of the dataset that used to call for dataset in repository
variantsetId	Σ	0..1	string	Id of the variantset that used to call for variantset in repository
readsetId	Σ	0..1	string	Id of the read
pointer	Σ	0..*	Reference(MolecularSequence)	Pointer to next atomic sequence
structureVariant	Σ	0..*	BackboneElement	Structural variant
variantType	Σ	0..1	CodeableConcept	Structural variant change type LOINC LL379-9 answerlist (Required)
exact	Σ	0..1	boolean	Does the structural variant have base pair resolution breakpoints?
length	Σ	0..1	integer	Structural variant length
outer	Σ	0..1	BackboneElement	Structural variant outer
start	Σ	0..1	integer	Structural variant outer start
end	Σ	0..1	integer	Structural variant outer end
inner	Σ	0..1	BackboneElement	Structural variant inner
start	Σ	0..1	integer	Structural variant inner start
end	Σ	0..1	integer	Structural variant inner end
Documentation for this format

10.10.2 Description

The MolecularSequence resource is designed for next-generation sequencing data. Patients’ observed sequences should be represented by recording reference sequence id/string and detected variants. To specify how it proceed, here is a picture below:

MolecularSequence.coordinateSystem: This element shall be constrained into only two possible values: 0 for 0-based system and 1 for 1-based system. Below is the picture that could explain what’s the difference between these two systems:

Here are two examples that clarify the usage in both cases (they represent same segment part):

• 0-based example: here Source:XML,JSON
• 1-based example: here Source:XML,JSON

MolecularSequence.referenceSeq: Four optional ways are provided to represent reference sequence in MolecularSequence resource:

1. MolecularSequence.referenceSeq.referenceSeqId: Reference sequence id in public database;
2. MolecularSequence.referenceSeq.referenceSeqString: Reference sequence string;
3. MolecularSequence.referenceSeq.referenceSeqPointer: Reference to observed sequence stored in another sequence entity;
4. MolecularSequence.referenceSeq.genomeBuild, MolecularSequence.reference.chromosome: The combination of genome build and chromosome.

The window selects a range from the reference sequence (or genome) that is used to define building block of a current sequence (e.g. MolecularSequence resource instance 1).

MolecularSequence.referenceSeq.strand: Only two possible values can be made by strand, +1 for plus strand while -1 for minus strand. Since the directionality of the sequence string might be represented in different word in different omics scenario, below are simple example of how to map other expressions into its correlated value:

Map to +1	Map to -1
5′-to-3′ direction	3′-to-5′ direction
Watson	Crick
Sense	Antisense
Positive	Negative

MolecularSequence.quality: Quality scores for bases in the sequence. It is intended to be compliant with emerging regulatory needs needs (eg: those found at PrecisionFDA ).

MolecularSequence.variant: This complex element is used for encoding sequence. When the information of reference sequence and variants are provided, the observed sequence will be derived.

10.10.2.1 Internal Pointers

MolecularSequence.patient: This element points to a Patient identifier to show that this sequence is related to the same patient.

MolecularSequence.specimen: A pointer to specimen identifier, if needed.

MolecularSequence.device: A pointer to Device identifier which is used for describing sequencing method (such as chip id, chip manufacturer etc.)

MolecularSequence.pointer: A pointer to a MolecularSequence instance for the next sequence block to build a sequence graph.

10.10.2.2 External Pointers

MolecularSequence.repository: This complex element is used to provide a clarifying structure, a base URL, and/or relevant IDs when referring to an external repository.

GA4GH Repository Example. If the MolecularSequence resource refers to a GA4GH repository for read info, references to a GA4GH full sequence dataset should conform to GA4GH data models and accessed via the GA4GH API. The URL of a GA4GH repository, ids of a GA4GH variant and read group are contained in the MolecularSequence resource. The URL of a GA4GH repository is an api_base of a GA4GH server that could be called for sequence data. The GA4GH variant set is a collection of call sets and the GA4GH call set is a collection of variant calls, typically for one sample. A variant call represents a determination of genotype with respect to that variant.

VariantSet definition: A VariantSet is a collection of variants and variant calls intended to be analyzed together.

CallSet definition: A CallSet is a collection of calls that were generated by the same analysis of the same sample.

A read group is a collection of reads produced by a sequencer. A read group set typically models reads corresponding to one sample, sequenced one way, and aligned one way. The API reference of Google Genomics is a GA4GH repository built by Google and provides details of the data models, such as the resource representations.

10.10.3 Usage Examples

10.10.3.1 Different way to represent sequence record with variations

We provide a detailed example to show how sequence resource can be used to represent record of observed sequence by different method.

The diagram above describes 4 optional ways provided in the MolecularSequence resource to encode sequencing data. Here are the corresponding examples

• By referenceSeqId Source:XML,JSON,TURTLE
• By referenceSeqString Source:XML,JSON,TURTLE
• By referenceSeqPointer Source:XML,JSON,TURTLE
• By Genomebuild+chromosome Source:XML,JSON,TURTLE

10.10.3.2 Example from precision FDA

We provide one example to show how precision FDA vcf data can be upload and comform FHIR specification, and how quality in sequence resource is represented by comparison between a reference sequence and the observed sequence.

Source: XML, JSON, Turtle.

10.10.3.3 Complex Variation example

We provide one example to show how a complex variant can be represented with the help of cigar. The deletion, insertion and mutation is represented in characters along with the number of repetition.

Source: XML, JSON, Turtle.

10.10 Relationship among MolecularSequence resource and genetics profiles

10.10.1 Pointers to MolecularSequence resource

MolecularSequence resource is used to transmit and represent sequencing data. In FHIR Genomics, there are several genetics profiles containing internal pointers to MolecularSequence resource for genetic data reporting. Here is the summary:

MolecularSequence.pointer: A bundle of MolecularSequence instances can be connected by MolecularSequence.pointer to build sequence graph described in Section 3. MolecularSequence.pointer will point to the next sequence block.

MolecularSequence extension in Observation-genetics profile: Observation-genetics profile is used to report a genetic variant found in patients. MolecularSequence extension contains a pointer to MolecularSequence identifier which has related sequencing read info. It will provide reference/observed allele information and quality scores for each base/sequence block.

10.10.2 Pointer to Observation resource (based on genetics profile)

Observation-genetics based Observation resource is used for interpretative genetic data. MolecularSequence resource and genetics profiles will use internal pointers to Observation-genetics-profile based Observation instance for variant report.

MolecularSequence.observation: A pointer to genetics Observation instance which is used for interpretations of this sequence block. Interpretations are generally about genetic variant found in this sequence block.

FamilyMemberHistory: A pointer to genetics Observation instance to report genetic test results of family member

10.10 Other Genomics Use Cases

During the development of the FHIR Genomics design, CGWG participants have commented on the earlier use cases and/or proposed new use cases. In this section, we list describe of these new cases and demonstrate how the proposed design will address them.

10.10.1 Get a patient’s family members genetics report

This example is proposed by Kevin Hughes. Family history is useful for clinicians to know more about the condition of the patient.

Get /FamilyMemberHistory?
    _profile=http://hl7.org/fhir/StructureDefinition/familymemberhistory-genetic&
    patient=123

10.10 Clinical Genomic Apps

The idea for a MolecularSequence resource grew out, in part, the SMART Platforms Project, which explored creating clinical genomic apps to integrated traditional EMR clinical data and genomic data to show data visualization and analysis, including CDS that depended upon both types of data. Below are a couple of examples. Several apps have already been designed including Genomics Advisor, SMART Precision Cancer Medicine, and Diabetes Bear EMR. Below, one of these apps will be described. To include other apps in this section, please feel free to add a note on it and how it uses FHIR/Genomics calls.

10.10.1 Genomics Advisor

The SMART on FHIR Genomics Advisor was an app incorporating genomics data to show risk of disease, drug susceptibility, and related conditions based upon genotype. Technically, this app was architected (see below) by combining data from independent data services, a SMART on FHIR clinical server for clinical information and one for a SMART on FHIR Genomics data server for genomic data. The set of FHIR API calls that are necessary to support this app are shown below:

The presentation of the app looks like this: