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OPEN Clinical Genome Data Model

(cGDM) provides Interactive
Clinical Decision Support for
Precision Medicine
1,2
Hyo Jung Kim , Hyeong Joon Kim1,2, Yoomi Park1, Woo Seung Lee1, Younggyun Lim1 &
Ju Han Kim1*
In light of recent developments in genomic technology and the rapid accumulation of genomic
information, a major transition toward precision medicine is anticipated. However, the clinical
applications of genomic information remain limited. This lag can be attributed to several complex
factors, including the knowledge gap between medical experts and bioinformaticians, the distance
between bioinformatics workflows and clinical practice, and the unique characteristics of genomic
data, which can make interpretation difficult. Here we present a novel genomic data model that
allows for more interactive support in clinical decision-making. Informational modelling was used as
a basis to design a communication scheme between sophisticated bioinformatics predictions and the
representative data relevant to a clinical decision. This study was conducted by a multidisciplinary
working group who carried out clinico-genomic workflow analysis and attribute extraction, through
Failure Mode and Effects Analysis (FMEA). Based on those results, a clinical genome data model
(cGDM) was developed with 8 entities and 46 attributes. The cGDM integrates reliability-related factors
that enable clinicians to access the reliability problem of each individual genetic test result as clinical
evidence. The proposed cGDM provides a data-layer infrastructure supporting the intellectual interplay
between medical experts and informed decision-making.

As the field of medicine transitions from experience-based medicine to data-driven medicine, an apparent par-
adigm shift to precision medicine is underway, driven by the development of technologies in fields including
medical information technology and computer engineering1,2. Genomic information is one of the most critical
components of precision medicine, given its power to explain individual variability3. However, the practical clin-
ical use of genomic information remains limited because its circulation is suboptimal, with each data processing
step tending to be independently performed and thus isolated. To narrow this gap, many organisations have
attempted to identify and develop methods to more effectively link genomic data to clinical information and
thereby facilitate its use4–6. However, several challenges must be surmounted before realising this goal.
First, a mismatch exists between the structure of genomic and clinical data. Genomic data based on
next-generation sequencing (NGS) technology is stored as a number of file types at various stages of the bioinformatics
analysis, with flexible file specifications to accommodate the broad range of research interests in bioinformatics7.
Raw genomic data can contain up to several tens of gigabytes of sequence information, each stored as a long string
of data, and therefore cannot be used directly in this form in clinical practice without further processing. Since
data processing to determine clinical relevance is both computationally intensive and time-consuming, genomic
information is not readily accessible relative to other types of clinical data. Thus, for precision medicine and per-
sonalised medicine, pre-processed genomic data need to be linked with other clinical information and provided
at the appropriate time. To resolve this issue, a structured database is needed to store and appropriately manage
genomic information for easy accessibility.
Second, genomic data have different properties than conventional observational data used in clinical set-
tings. Therefore, genomic data must be clarified by considering procedural dimensions. Since genomic workflows

1
Seoul National University Biomedical Informatics (SNUBI), Division of Biomedical Informatics, Seoul National
University College of Medicine, Seoul, Republic of Korea. 2These authors contributed equally: Hyo Jung Kim and
Hyeong Joon Kim. *email: [email protected]

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Figure 1. Data-level linkage structure between conventional HIS and GIS. From a software engineering
perspective, a comprehensive hospital information system comprises components that represent separated
data collection routes and distinguishing characters of the data. We suggest the concept of GIS to illustrate the
implementation of the cGDM. This architecture supports both information and functional integration, even
with existing clinical information systems.

contain a large number of pipelines for information processing, significant differences between the interpretation
of processed data and data obtained from different information systems relative to the clinical workflow is inev-
itable8. Accordingly, a robust data model is required to serve as an information system to systematically man-
age genomic data, encompassing the detailed processes of data processing, analysis, and filtering. Additionally,
information on the reliability and accuracy of these analyses results, along with the detailed analytical process
and equipment used, must also be systematically stored and managed, as it is an essential criterion for clinical
decision-making9. Moreover, because genomic data is less variable than observational data, information integra-
tion will allow for maximisation of the utility of the collected genomic information for clinical use.
The third challenge majorly hindering the integration of genomic data with clinical information is difficulty in
mapping the two types of data for medical interpretation. The presence of biomarkers for specific diseases or drug
reactions is a critical factor in clinical decision-making10. In the case of targeted sequencing, the data processor
is informed about biomarkers related to the panel prior to analysis. In clinical practice, reannotation of patient
genetic information according to updated biomarker discoveries from the biomedical research community is
continuously required at the population level. Thus, a structured data model with consistent data representation
would enable the rapid adoption of both evolving biomedical knowledge and individual medical records, which
can be delivered to the point of care through agile data processing. Furthermore, patient genomic data expressing
specific biomarkers should be readily accessible from the information system along with clinician-confirmed
interpretations11.
Personal-health status can be converted to a composition of multi-layered, multi-dimensional digitalised
information for utilisation in an information system that facilitates handling big data (Fig. 1). Indeed, vast
amounts of data and associated metadata from multiple medical measuring technologies, such as laboratory tests
or imaging studies, have already been successfully merged in clinical information systems. Overall, although
genomic information represents the most sound and intensive health-related signals provided by the human body
throughout life, the weak links to medical practice highlighted above contribute to its underutilisation in clinical
decision-making. Therefore, it is necessary to effectively link and integrate clinical information with personal
genomic information, helping to accelerate the shift to personalised medicine.
Toward this goal, we aimed to develop a clinical genome data model allowing for enhanced interactive sup-
port in clinical decision-making, which minimises the possibility of misinterpretation at the point of care, due
to formal and procedural heterogeneity related to the production process. We began by redefining the obstacles
to the spread of genomic information into routine care, including problems relating to the reliability of measure-
ments that could cause hesitation in clinical decision-making and data structural problems that have hindered
integration of genomic data into existing information systems. From a clinical perspective, we focussed on
clarifying not only the problem of heterogeneous data structure issues but also reliability-related factors. In this
context, we operationally defined a bioinformatics process not as a “measurement”, but rather as a “production”
requiring transition a physical form of existence to a human-interpretable representation. Thus, informational
modelling based on workflow analysis was used as a ground knowledge for a communication scheme between
sophisticated bioinformatics products and a representative component of data, which is essential for a proper
clinical decision.

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Figure 2. Data flowchart based on a next-generation sequencing workflow. The objects shown in this diagram
are classified into three class types- ‘Action’, ‘Information’, and ‘Entity’. ‘Action’ was first posted with respect to
what occurred in each expert domain and the resulting ‘Information’ was displayed as a result of each action.
Finally, ‘Entity’ was defined as the captured information class at each stage of the workflow. Subtypes of ‘Variant
Information’ were drawn scalable to accommodate the potential extension of subclasses.

Results
This section primarily consists of Failure Mode and Effects Analysis (FMEA) results and entity-attribute model-
ling. FMEA output is presented in two diagrams: a dataflow diagram that focusses on the derivation of the con-
tents of the genetic test based on NGS sequencing technology, and an information process map that extends the
viewpoint to the level of clinico-genomic context. At this step, the protocol entity of the former dataflow diagram
was subclassified to reveal the procedural dimension in information processing. Moreover, the set of attributes
involved in each step of information transfer was identified. Finally, the cGDM are suggested as a result of struc-
tured data modelling based on the attribute set.

Dataflow diagram based on an NGS workflow. A workflow diagram was derived in order to illustrate
the data flow in which the genomic information inherent in the human body is converted to a genomic test result.
(Fig. 2.) At this stage, the clinical view is minimised, with both the flow of information and the process of analys-
ing the specimen after the sample collection across experimental laboratory and computational analysis drawn
on a large scale.
The subtypes of processed variant information in the parallel structure, used to cope with the growing body of
knowledge in bioinformatics, are listed at the bottom of Fig. 2. Variant information can be called in multiple types
depending on the perspective and purpose of the analysis. For example, there are four types of genetic variation:
single nucleotide variation (SNV), small insertion/deletion (InDel), copy number variation (CNV), and translo-
cation/fusion. There are predictive biomarkers as well such as microsatellite instability (MSI) and tumour muta-
tion burden (TMB). As the amount of NGS technology-based knowledge increases, more subclasses representing
novel perspectives can be added. Scalable data modelling to support the differentiation of knowledge over time
is essential not only for expressiveness, but also for reducing the burden of information systems maintenance.
In summary, we linked the separate offline workflows at this step that occurred in different places until
genomic data could be provided as processed data. The workflow diagram provided the basis for detailed analysis
and discussion.

Extending the NGS process under a clinico-genomic context. After establishing consensus on a
larger scale, we extended the flow of information to the clinical context in detail. At this stage, the standpoint of
the workflow analysis was clinical decision making. Hence, the workflow diagram started with a clinical deci-
sion. We extended the flow between several actions in the clinico-genomic context involving multiple entities
identified, and detailed analysis was performed. In this process, the output data file format and detailed processes
for handling output files, along with the tools required for linking to external knowledge databases, are also
described.
The working group discussed mechanisms for extraction of the entity-attribute set which would avoid prob-
able information distortion and omission. We considered that the genomic data model for clinical use should be
the knowledge communication scheme, thus preserving its reliability-related factors. At a minimum, the genomic
data model must provide sufficient information to decide whether the confidence level of the genomic test result
justifies its consideration as clinical evidence. For this function, failure was defined as that which causes mis-
interpretation or non-use of the genomic data for clinical decision. The process of producing clinical evidence
from genomic data at the bioinformatics area (Fig. 3) shows a pattern that is a series of repeated representations
of information converted by reference knowledge bases and data processing rules. Thus, failure modes can be
classified as incomplete specifications in three meta-categories: origin, reference, or symbol. Due to the nature of

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Figure 3. Failure mode identification: mapped next-generation sequencing process extended to a clinico-
genomic context. In the bioinformatics area (cyan background), information may be distorted by the
insufficient representation of origin, processing rule, and external reference. To prevent this failure,
identification and semantics, related attributes are listed under the boxes. In the clinical area (yellow
background), the data model functions as a communication scheme for the collaborative process implemented
in the hospital information system. Data-level integration facilitates just-in-time queries and reuse of data.

the semantic interpretation, any fragmentation of symbol causes not only loss of information but also assignment
information to direct the origin12,13.
We conducted workflow analysis to extrapolate general descriptors of the related attributes with the goal
of preserving information during production and delivery processes from clinical intention to clinical uti-
lisation. Figure 3 provides a more detailed data-level view, including how genomic information is realised as
clinical evidence in a case based on a structured data model. The structured genome data model can support a
report via presentation on a variety of transcription forms (report forms), which are optimised for initial intent.
Furthermore, additional utilisation paths are accessible in the clinical-information system. As shown in Fig. 3,
data-level integration helps the amplification of the incidental utilisation. (Supplementary Fig. 3) To illustrate,
consider a patient who orders whole-genome sequencing to screen for cancer biomarkers at their first visit. When
the patient receives a prescription for antibiotics a year later at a visit for other symptoms, that same genomic
test result can be re-used from a pharmacogenomics perspective for safer and more efficient drug prescription.
The clinical decision support system plays a vital role by just-in-time display of the matching information with
pre-defined rule and knowledge-based processing6,14,15. A computational genome data model is a prerequisite for
this implementation15–17. Finally, we introduce a logical data model in the next step of the study.

The cGDM. Logical data structuring with the entity-attribute model. Finally, the cGDM was designed as
an entity-attribute model consisting of 8 entities and 46 attributes (Fig. 4). For a structured data model of the
identified clinico-genomic attributes, logical modelling was conducted to ensure data-level linkage with conven-
tional primary clinical databases. In order to define the entity-attribute model based on the action and collected
data, tool/processor classes and the attributes of each class from Fig. 3, we define 3 types of classes as protocol
and related attributes (Table 1). Since the cGDM is designed to support data-level integration with the existing
system, only the minimum subject identifier is defined as ‘linkage identifier to clinical information’. To represent
the procedural dimension, which is stressed in the study, we combined two workflow analyses on different scales.
For example, the entity ‘Protocol’ as a part of the procedural dimension is explicitly represented in Fig. 2, then
expressed again as a list of lower steps in Fig. 3. Since clinical observation is typically considered as the collection
of events18, the logical composition of the date/time and actor identifier related to the clinico-genomic context
were declared.
The derived classes and entities in Table 1 were used to declare final entities and attributes in the cGDM
(Fig. 4). The mapped Actions and Action-related classes (Collected Data and Tool/Processor) are categorized
into subdomains and related attributes for each step in Table 1. In Table 1, an action and its result are grouped
into one step, and the related attributes are represented by the attributes classified in the corresponding step.
For normalization, related attributes are categorized to create one or more new groups called entities for each
step, and they are the basis for defining ‘Entities’ in the Entity-Attribute model (Fig. 4). For example, ‘Physical
information according to coordinate system’ is one of the three subdomains of the action ‘Sequence Annotation’.
It can include an attribute set include an attribute set (Cytogenic location, Codon, Exon) representing physical

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Figure 4. The Clinical Genome Data Model: Structured data modelling with entities and attributes. The cGDM
is designed as a logical data model of 8 entities and 46 attributes. The objects and related attributes derived
through FMEA are integrated into a logical data model through abstraction and normalisation.

location information for each variant. However, this “Physical information according to coordinate system” can
be a subdomain in other steps besides “Sequence Annotation”. And even though it is the same subdomain, the
related-attribute set may be different depending on which step or action. In summary, each step identified in the
entire clinico-genomic process can include multiple entities, and one entity can be related to multiple steps. Even
in the same entity, the configuration of related attribute as a factor affecting each step may vary from step to step.

Enhancing the reliability of genomic data by the cGDM. We conducted additional analyses to evaluate whether
the cGDM can represent sufficient information scale to access the reliability of delivered information. We classi-
fied three selected examples of errors that often occur in genomic data processing into two distinct types: insuf-
ficient information scales and multiple names for the same variant. We then checked whether process errors of
these types could be covered by the cGDM.

Insufficient information scale to detect clinically significant genetic variation. In this category, we discuss two typ-
ical errors: the absence of RefSeq accessions and versions in Human Genome Variation Society (HGVS) nomen-
clature, and nonexistence in human genome reference assembly. Both are cases in which the information scale is
insufficient for the detection of clinically significant genetic variations.
Refseq accessions and versions for HGVS nomenclature. In the first example, a genetic biomarker has the
potential to be clinically utilised for diagnosis, prognostics, and prevention19,20. The conventional way to represent
genetic biomarkers is by protein-level HGVS nomenclature, which describes amino-acid sequence changes21,22.
According to standard nomenclature recommendations of the HGVS, a RefSeq accession and version number
are required, followed by information on amino-acid sequence changes. However, since the expression has usu-
ally been used without the accompanying reference sequence information upon which the numbering system is
defined, this incomplete representation leads to a misinterpretation of the results for use in real clinical settings.
For example, the BRAF V600E mutation is the most common driver in melanoma23. This BRAF mutation is
represented as ‘NP_004324.2:p.V600E’ with the corrected version of the nucleotide sequence, but was formerly
expressed as ‘NP_004324:p.V599E’ based on the nucleotide sequence missing a codon in exon 124. Because V600E
is recognised as a biomarker in the majority of publications, V599E without reference sequence information has
been detected as a distinct mutation. To reduce such discrepancies, the proposed cGDM implements a more
complete set of elements: the RefSeq accession, version number, and amino acid changes. Since the purpose of
the cGDM is to eliminate ambiguity in information delivery, the set of attributes needed to point out a particular
mutation is declared. Thus, the cGDM enables more reliable query result suggestions, even when the inputted

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Class
Seq. Action Collected Data Tool/Processor Related Attribute Entity
Institution Identifier Subject
Linkage Identifier to Clinical
Identifier Test Identifier (Order ID
Information
or Accession No)
1 Sample Collection Submission Date Timeline Information
Medical Institution Actor Information
Clinician
2 Specimen
Experiment Related
3 Machine Sequencing Test Description
Information
Type of Sequence
Platform technology
Sequencer
Collection Date Timeline Information
Sequencing Institution Actor Information
Experimenter
4 Read File
Physical(Location)
Position Reference allele
5 Alignment information according to
Alternative allele Chromosome
coordinate system
Analytics Institution Actor Information
Bioinformatician
Initial
6
Alignment File
Physical(Location)
7 InDel Realignment Position’ information according to
coordinate system
/ Reference allele’
Base Recalibration Alternative allele’
Chromosome’
Base quality(>Q20) Quality Check information
(Average) Depth of coverage
Mapping Quality (%Mapped reads)
Received Date Timeline Information
Analytics Institution Actor Information
Bioinformatician
Adjusted
8
Alignment File
9 Variant Calling Hetero-/Homozygosity Genotype Expressions
Phasing information
Missing
Analytics Institution Actor Information
Bioinformatician
10 Variant Caller Tool Pipeline information
Step
Parameter
Origin Data source
Version
Build
Parameter
11 Variant File
Gene (HGNC Gene Symbol, Entrez Variant Descriptive
12 Sequence Annotation
ID, Ensembl ID) Expressions
Variant (HGVS(genomic, coding,
protein change + version), dbSNP,
dbVar)
Physical(Location)
Cytogenetic location information according to
coordinate system
Codon
Exon
ClinVar, COSMIC ID Functional Annotation

Continued

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Class
Seq. Action Collected Data Tool/Processor Related Attribute Entity
Molecular Effect
Variant Type
Functional Domain
Analytics Institution Actor Information
Bioinformatician
13 Annotator Tool Pipeline information
Step
Parameter
Origin Data source
Version
Build
Annotated
14
Variant File
15 Clinical Annotation ACMG actionable genes Clinical Annotation
FDA qualified biomarkers
User-defined biomarkers
Analytics Institution Actor Information
Bioinformatician
Documentation Date Timeline Information

Table 1. Extracted classes and related attribute sets from each step of clinico-genomic context for the Entity-
Attribute model. The processes in the clinico-genomic workflow shown in Fig. 2 are listed in order and
associated with the classes, related attribute sets for each process. This table is an intermediate result between
the result of FMEA and the final logical model. Derived related attributes are abstracted within each class and
grouped into entities.

search term is fragmented. Supplementary Figure 2 demonstrates a scenario in which a clinician performs a
semantic query on a melanoma patient in a cGDM system. Importantly, the cGDM links the extracted annotation
information to the results that the clinician would like to retrieve.
Human genome reference assembly. In the second example, the most popular way to determine genetic vari-
ants in standard NGS analyses is resequencing, which identifies variations by aligning reads against the reference
genome sequence25,26. However, this often causes assembly errors. Since a variant position designates a relative
location based on a given reference sequence, the data sources to which the reads are aligned are necessarily
required. For example, the genomic position of BRAF V600E, chr7:140453136 A > T (GRCh37), is shifted into
chr7:140753336 A > T (GRCh38) as that the significant reference coordinate has changed. Therefore, the cGDM is
designed to specify the reference data sources, including assembly, version, and origin, greatly reducing reference
compatibility problems induced by fragmented information.

Unnormalised representation of genetic variants. Non-unique expression of insertion and deletion. The second
main error type involves the standardised representation of genetic variants, for which we exemplify issues arising
due to the multiple names associated with the same insertions and deletions in databases. Variant Call Format
(VCF) is a file format that allows for a flexible representation of different types of variations. Since each variant
caller reports in a slightly different manner, the same variant could be represented in non-unique ways27. These
inconsistencies across tools hamper the robust identification of clinically significant variants28. Thus, a specifica-
tion for the unified representation of genetic variants is in high demand. For example, chr10:11805838 C > CT and
chr10:11805838 CG > CTG represent the same insertion, even though they are not represented by the same text
string. To overcome the issue, when importing VCFs into the cGDM, the representation of variants is converted
into their minimal representation via tools such as vcflib vcfallelelicprititives or GATK LeftAlignAndTrimVariants.
This process establishes consistency between internal and external representations and provides a standardised
variant representation to ensure accurate and consistent identification of clinically significant variants.
The two types of problems described above can be solved using the entities and attributes defined in the
cGDM. In solving the first problem of an insufficient information scale, the primary challenge is securing an
element set that can convey the complete sense when expressing specific information. In the cGDM, since all fac-
tors causing this problem are represented by an entity-attribute set, no loss of information occurs. In the second
type of problem, our example highlighted that models can be derived from the same semantics despite different
nomenclature (syntax) in the stored values.
Detailed considerations made in this section highlight the differences in perspectives between the bioinfor-
maticians and clinicians participating in the working group on the clinico-genomics workflow. The cGDM was
placed in this interspace for systematic information management, with the application of reliability engineering
to reduce miscommunication and distortion arising from a difference of viewpoint between experts in different
fields.

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Database
Internal database Demo database
Cancer TCGA TCGA 1000 Genome TCGA
Table name Panel Leukemia Depression COAD LUAD Phase 3 CEU PAAD
CLINICAL_IDENTIFIER 10 503 1000 459 522 99 155
EXPERIMENT_RELATED_INFORMATION 10 517 1000 459 522 99 155
BIOINFORMATICS_PROTOCOL_RELATED_INFORMATION 10 517 1000 459 522 99 155
Row counts
GENOMIC_ALTERATION 2733 29,279,631 842,199,347 361,933 318,947 229,525,363 56,159
(per table)
MICROSATELLITE_INSTABILITY 0 0 0 0 0 0 775
CLINICAL_ANNOTATION 40 267 108 123 97 1 12
QUALITY_CHECK 10 517 1000 0 0 0 0
Data volume (per database) 2MB 8.2GB 144.7GB 48.37MB 42.63MB 47.67GB 9.41MB

Table 2. Summary of imported genomic data from various data sources in cGDM databases. The databases are
categorised into internal and demo database. The specifications of the database tables are informed in Table 1. This
table presents row counts of each database table and data volumes of each database. The internal databases include
3 private datasets (cancer panel, leukemia and depression) and 2 public datasets (TCGA COAD and TCGA
LUAD). The demo databases include 2 public datasets (1000 Genome Phase3 CEU and TCGA PAAD). * COAD is
study abbreviation in the TCGA stands for Colon adenocarcinom a; LUAD for Lung adenocarcinoma.

Validation of the cGDM. Here, the cGDM was finalized in the form of a logical model, which allows adap-
tation to the diverse development environments of existing heterogeneous clinical information systems. Logical
model can play an essential role to generalize the complex phenomenon by abstraction and enhance under-
standing core ideas the model deliver between different stakeholders of in the complex system29. Whereas, the
drawback of this approach is that physical modelling layer is needed in order to the data model implementation
and validation. Thus, we design a physical data model implemented in a relational database to evaluate the model
validity for real-world data and to proof of concept how implementation of the cGDM enables interactive clinical
decision support in clinical information system shown as Fig. 3 (Left side; Clinical decision support system for
incidental utilization).

Implementation of the real world data. This physical data model of the cGDM is provided in forms of
entity-relationship diagram and table (Supplementary Information Table 1; Fig. 2). Also, one-click executable
data definition language script is also freely accessible on a web page (https://github.com/SNUBI-HyojungKim/
cGDM-Clinical-Genome-Data-Model).
For the data model validation with real-world data, we built pilot databases based on the cGDM and uploaded
genomic data of over 2,000 patients for multiple diseases, including acute lymphoblastic leukemia, solid cancers,
and depression cases (Table 2, internal databases). However, the pilot datasets related researches remain undergo-
ing, we have built two representative demo datasets for open source (Table 2, demo databases) 1000 genome CEU
(Utah Residents with Northern and Western European Ancestry) population dataset for whole genome sequenc-
ing (n = 99, 47.67 GB), 2) TCGA PAAD (Pancreatic Adenocarcinoma) dataset for somatic mutation (n = 155,
9.41 MB). We believe those well-known public dataset have advantages on data validation issue. Every demo
datasets and source codes are freely available from at the Github page as mentioned above.

How implementation of the cGDM enables interactive clinical decision support. One of the major challenges of
healthcare informatics is supporting clinicians who need to handle constantly evolving knowledge and inher-
ently complex genomic data. Patient genomic data in a static document format or in structured model but in
which has vague designation of the variant limits functionality of clinico-genomic information system30. The
cGDM could address the issue by working as a data-level infrastructure for interactive clinical decision support
along with external knowledge bases (Fig. 5). For the cGDM’s programmability test, we developed a pharmacog-
enomic clinical decision support function running on the cGDM database which reflects the knowledge of the
IWPC warfarin dosing algorithm. The source code is freely available at https://github.com/SNUBI-HyojungKim/
cGDM-Clinical-Genome-Data-Model. Supplementary Figure 3 illustrates both of logical information flow in
back-end system and its appearance on the user interface.

Discussion
The rapid accumulation of genomic information has led to a paradigm shift in medicine. However, significant bar-
riers remain to overcome for the widespread clinical exploitation of this information. Through multi-disciplinary
analysis and consideration of this phenomenon, we identified two main causes: first, reliability-related result
variance among numerous pipelines and processes; and second, the unique data structure of genome informa-
tion. Since these two causes have shared influences, an integrative solution is likely to be more effective than a
point solution. Moreover, we foresee that GIS will become an essential component of an integrated clinical infor-
mation system in the precision medicine era. In this context, this cGDM could serve as a genomic information

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Figure 5. The conceptual map of a genomic decision support system based on the cGDM. While the
accumulation of confirmatory knowledge could seem relatively slow compared to the speed of the vast
discovery of the bioinformatics field, the benefits and impacts the two will have on patients when they are
seamlessly connected are evident. The cGDM brings this process into computational space.

representation scheme enabling the intellectual interaction between medical experts and informed decision mak-
ing, ultimately contributing to the enhancement of personal genomic data utilisation at the point of care.
To ensure the convenient and appropriate clinical use of genomic data, medical informatics technology is
needed as part of the infrastructure supporting the integration of clinic and genomic layers of information31,32
Given the multi-level and multi-dimensional nature of health, clinicians must perform decision-making for a
given case based on a collection of segmented data representing a person’s health, including laboratory data,
imaging, and observation data assessed by experts. Currently, a clinical information system is typically used as a
core tool for supporting this knowledge in a management process. To broaden perspectives in the era of precision
medicine, we propose a genome information system (GIS) as an integral component of an integrated clinical
information system (Fig. 1).
The cGDM can serve as a data-level infrastructure for implementation of the GIS. When decision makers face
unfamiliar health-status measurements, determining clinical significance and meaning is challenging32,33. The
cGDM was designed to preserve genomic information at an appropriate information scale and granularity cover-
ing the procedural dimension, which is related to the confidence level as a clinical measurement for clinical appli-
cation. The design of the cGDM allows processed genomic data for a general purpose to be stored and merged
with existing clinical data, providing outputs in an interoperable data format. Likewise, sequencing analysis, data
processing, and presentation of processed information can be managed in a form that can be explicitly confirmed.
Once data are uploaded to the cGDM-based database, they serve as a supportive backbone for any downstream
functional applications such as report generation or a clinical decision support system. (e.g. Supplementary Fig. 2;
Fig. 4) To develop a system for the systematic management of genomic data, it is necessary to unify its data struc-
ture with that of other existing components of clinical information systems, ensuring sufficient reliability for
identifying the original data generation process34.
Conventional systems have focussed on data structure unification issues first, to harmonise heterogeneous
systems among separate institutions35. By contrast, our model was designed to achieve both clinico-genomic
knowledge representation accompanied by traceability of the genomic data, to enable determination the clin-
ical significance of a genomic test result provided to a clinician. To allow better assessment of the meaning-
fulness of genomic information, we defined the basis for each attribute and focused on designing an entity set
that accurately represents the genomic data that are delivered to the target user, without information distortion.
Furthermore, the cGDM is adaptable as a data-level extension to any existing information system, regardless of
database system or application platform.
Accumulation of basic, translational, and regulatory science is a prerequisite to implementing personalised
medicine in routine care36. As a basic science, bioinformatics has witnessed explosive and rapid progress since

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the completion of the Human Genome Project. In the context of regulatory science, there are currently several
ongoing efforts within the bioinformatics and molecular biology domains10–12, with great maturation in the body
of knowledge during the last decade, including principles and recommendations related to NGS technology.
These efforts have focussed primarily on the standardisation of bioinformatics protocols and the file structures
for intra- or interlaboratory communication.
Translational science represents the next challenge for the realisation of actual health promotion with per-
sonalised medicine37. In the context of clinico-genomics, translational approaches ultimately target the syntactic
and semantic interoperability between genomics and clinical practice, to ensure business continuity in terms of
knowledge management37–39. Previous approaches have stressed a need for structural transformation to overcome
the currently low adaptation of genomic information for clinical decision-making. However, the other major
cause, the knowledge gap, has yet to be seriously considered because the solution appears obvious: the education
of medical experts in bioinformatics principles.
Nevertheless, this raises the question of the specific level of bioinformatics knowledge required in clinical
practice. Our working group agreed that clinicians do not need to be bioinformatics experts to implement pre-
cision medicine. Preferably, the key is education on how to understand genomic data and confidence levels, and
then be provided with sufficient information to make clinical decisions. Based on this perspective, we identified a
previously unrecognised ambiguity related to the knowledge interplay between bioinformatics and medical prac-
tices (Fig. 3). Although the genome is the most concrete type of observational data representing an individual’s
inheritance, the genomic information delivered to clinicians is rarely transformed to a human-readable form and
is also rarely a direct representation of the genomic sequence. Instead, this information is more of an intellectual
product, processed in a purpose-weighted result file structure. Thus, the question of reliability of the genomic
information must be addressed before it is adopted by the physician, similar to other types of conventional obser-
vational data.
Considering the knowledge gap in this clinico-genomic context, unrecognised ambiguities may occur on each
side. For example, when linking the outputs of bioinformatics to clinical fields, the indicator of information qual-
ity moves from internal consistency within the same protocol to external consistency between different protocols.
Thus, to accomplish the final goal of precision medicine, more discussion is needed about how data will cross this
intermediate space, then about how to best represent and deliver crossover information.
To best of our knowledge, the methodology proposed herein has not yet been applied in the field of genetic
information processing. FMEA is the most commonly used methodology for determining reliability of manufac-
turing and design processes15–19. We perceive the result of genetic testing not as an output of static measurement,
but rather as an output of an intellectual production process. When conducting bioinformatics analyses, there is
no requirement for unification among the processes, since the internal consistency within each process guaran-
tees scientific rigour. Moreover, the flexible data specifications used in the bioinformatics field have the advantage
of supporting various research applications7, but that advantage becomes an obstacle to data integration for com-
prehensive clinical decision making. In addition, relevant external knowledge, tools, platforms, and analytical
techniques cannot be unified because they are still under development. Considering this large interdisciplinary
hyperspace, our approach aims to improve the quality of information delivery while responding to an enormous,
growing body of knowledge that has yet to be integrated within its own basic-science field. Therefore, the FMEA
was adopted to derive and clarify a set of metadata designed to prevent information from being distorted.
To facilitate the use of genomic test results in clinical practice, it is essential to integrate genomic data into
clinical decision support systems regarding data volume and knowledge management6,14,15,17. Data modelling
is the first and most crucial step in the multi-tiered design of information systems. The final product reliability,
for example specific clinical decision support algorithms or integrated information systems, is hardly improved
over the designed reliability on the lower level of architecture (data-level)40. This viewpoint was projected to
the study design. An important consideration is that the analytic scheme presented here can help to enhance
clinico-genomic understanding for experts on both the medical and bioinformatics sides of the workflow. (see
Methods Section) Throughout the development of this method, we focussed on equally weighting the clinical
perspective and bioinformatics process analysis in the context of business continuity, starting from our initial
clinical intention through bioinformatics information processing by a knowledge-based protocol, finally offering
a deliverable and interpretable form to the point-of-care clinician.
The methods, equipment, data processing and analytical techniques for extracting data from targets in nature
will continue to evolve and accumulate. The cGDM was designed to be flexible and able to readily adapt to tech-
nological changes. However, an eventual failure in responding to these changes cannot be excluded and represents
a potential limitation of this study.
Several standard models have been generated, based on differences in data scale and technical maturity, prior
to the development of NGS technology. Thus, we have not considered multi-omics data. Focussing on NGS
technology-based workflow helped us to determine an optimised information scale and granularity for the clini-
cal level, and to design a model to generalise and process genomic data based on individual patients. The cGDM
could be extended to be a part of technology-wide data model integration for multi-omics data management.
The data model proposed in this study aims to clarify blind points within the interdisciplinary genomic-clinical
interface, connecting separated expertise within a single platform to provide a broad perspective that covers the
information reliability required for clinical evidence. In particular, we have made a novel attempt to adopt the
FMEA method for a systematic meta-level data design process. Future work will focus on the development of
functional systems to conduct real-world validation, including a data-upload pipeline from processed genome
data files, as well as a clinical decision support tools based on the cGDM. Results of this exercise are planned to
be released in a further study.

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Methods
Material: The production process of bringing genomic information to bedside care. Here, we
define a genomic test as a series of team-based information production processes, in which the meaning of the
information is expanded, represented, and reproduced by reference to an external knowledge base, rather than
through direct extraction of inherent information. Despite the invariant nature of a personal genome, genomic
information presented to a clinician may vary according to specific processing protocols adopted7,25,26,41. This
variability raises reliability issues for the use of genomic test results as clinical evidence42.
As artefacts from production, genome information processed for clinical use may pose a likelihood of misinter-
pretation due to information distortion, omissions, and fragmented senses. Furthermore, information reliability
is a critical factor determining the ability of clinicians to utilise the genomic information43. Thus, our approach in
developing this cGDM for focussed on the multi-dimensional scope of information, including procedural factors,
derived from NGS technology.

FMEA: An attribute-clarified framework. FMEA is a systematic prospective risk factor analysis

approach that predicts and prevents possible errors, improving quality across team-based processes44. When used
for advanced investigation, the method has advantages enabling exploration of uncertain, unforeseen complex
workflows at an early stage45,46. Since its introduction in 1963, broad subtype applications of FMEA have been
performed in broad domains including reliability engineering40,47, behaviour modelling48, software engineering49,
conceptual design50, and knowledge management and representation51,52. In particular, FMEA has been applied
as a method of knowledge representation to extract process reliability related attributes and to structure and
map entities and attributes48,52–54. In this study, the FMEA approach was adopted for workflow analysis and the
attribute-extracting method.

The working group. A multidisciplinary expert team was formed from the areas of bioinformatics, medical infor-
matics, and medicine. The participants included three bioinformaticians, two medical informaticians with clinical
informatics and application expertise, and one medical doctor. The medical doctor has experience in both clin-
ical practice and conducting translational research from the perspective of both biomedical science and clinical
practice.

Workflow analysis. Over a period of nine months, process mapping, failure identification, and related attribute
extraction were conducted using FMEA at over 18 team meetings. Structured data modelling for enhancement
of data accessibility was then conducted using a logical data model, with the attribute set derived from the FMEA
workflow diagram.
We chose the conventional FMEA workflow analysis40,47 and adapted it for cGDM development. Conventional
FMEA consists of two main steps. First, the failure mode is identified through (1) assembling a multi-disciplinary
team with at least one expert from each domain over the target production process, (2) combining components
and process function in order to derive a workflow diagram, and (3) listing the modes that may lead to failure
at each step. The second part involves modifying the process itself with consideration of priority, including (1)
evaluating the severity and occurrence ranking of each failure mode and (2) proposing a modified workflow or
audition guideline.
In this study, risk estimation and priority-scoring steps were not designed, since our purpose was to review
the fragment of metadata composition that may cause unintended information distortion or misinterpretation.

Logical data modelling. Data models are the basis of computation ability for intelligent information
systems55. The database design process can generally be divided into logical and physical database design56. The
physical data model requires a clear and specific description over logical design, which depends on the existing
development environment. Thus, we designed this cGDM as a logical data model based on the FMEA results to
support data-level integration with any existing clinical information systems.
Logical data modelling methods are comprised of abstraction and normalisation. Database abstraction refers
to aggregation and generalisation that occur at the points of intersection57. We first abstracted the attributes
derived from FMEA and expressed the factors corresponding to each step in the workflow. Then, normalisation
was performed to prevent duplication and inconsistency of data elements considering their names, scale and
relations.

Demo datasets for the real-world data implementation. Two of representative public accessible
datasets are selected for the development of the demo databases: The 1000 Genomes Project of the International
Genome Sample Resource (IGSR) with population code “CEU” (Utah Residents with Northern and Western
European Ancestry)58, the pancreatic cancer data from The Cancer Genome Atlas (TCGA_PAAD)59.
Collected datasets were VCF and MAF file format and Extract-Transformation-Load (ETL) process of the
genomic data was performed by two bioinformaticians with Python 2.7.16. ANNOVAR 2016Oct2460 version
was used as a clinical annotation tool for 1000 Genome Project CEU dataset. The result datasets were imported
in a table within the MySQL server database by two medical informaticians. We ran the SQL scripts in MySQL
5.6.46 on a Server with 8GB of RAM and an NVIDIA tesla c1060 / Quad core CPU running run on CentOS Linux
release 7.7.1908. The final outputs took the form of SQL tables and functions61–63.

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Data availability
The description of the internal datasets and demo datasets used in this work are summarized in Table 2. The
internal datasets are available from the corresponding author on reasonable request. All public data utilized in
this work are TCGA COAD, TCGA LUAD, TCGA PAAD (https://portal.gdc.cancer.gov/) and 1000 Genome
Phase 3 CEU (https://www.internationalgenome.org/category/phase-3/). TCGA PAAD and 1000 Genome Phase
3 CEU are built in forms of the cGDM DB and shared as demo databases (available at https://github.com/SNUBI-
HyojungKim/cGDM-Clinical-Genome-Data-Model). This repository contains Data-Definition-Language
(DDL), two demo databases based on cGDM containing public data and a PGx CDS example source code in the
case of IWPC warfarin dosing.

Received: 21 February 2019; Accepted: 9 January 2020;

Published: xx xx xxxx

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Acknowledgements
This research was supported by a grant (16183MFDS541) from the Ministry of Food and Drug Safety in 2018. We
thank Dr. Kelsey Caetano-Anolles for discussions during the writing of this paper and Dr. Seung Suk Nam for his
advice on the philosophy of linguistics.

Author contributions
Conception and design: Hyo J.K., Y.P., Hyeong J.K. and J.H.K. Study supervision and administrative support:
J.H.K. Performing FMEA methods and discussion: Hyo J.K., Hyeong J.K., Y.P., J.H.K., W.S.L. and Y.L. Design
entity-attribute model: Hyo J.K., Hyeong J.K., Y.P., and J.H.K. Build demo database and development of the source
code: Hyeong J.K., Hyo J.K., W.S.L., and Y.L. Wrote the manuscript: Hyeong J.K., Hyo J.K. and Y.P. All authors
read and approved the final manuscript.

Competing interests
The authors declare no competing interests.

Additional information
Supplementary information is available for this paper at https://doi.org/10.1038/s41598-020-58088-2.
Correspondence and requests for materials should be addressed to J.H.K.
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