=Paper=
{{Paper
|id=None
|storemode=property
|title=Ontology modeling of genetic susceptibility to adverse events following vaccination
|pdfUrl=https://ceur-ws.org/Vol-1061/Paper3_vdos2013.pdf
|volume=Vol-1061
|dblpUrl=https://dblp.org/rec/conf/icbo/LinH13
}}
==Ontology modeling of genetic susceptibility to adverse events following vaccination==
https://ceur-ws.org/Vol-1061/Paper3_vdos2013.pdf
Ontology modeling of genetic susceptibility to adverse events following vaccination
Ontology modeling of genetic susceptibility to adverse events
following vaccination
Yu Lin, Yongqun He
Unit for Laboratory Animal Medicine, Department of Microbiology and Immunology, Center for Computational Medicine and
Bioinformatics, and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA
ABSTRACT may be quite common in the healthy population. Moreover,
Administration of different vaccines triggers a variety of adverse events the main determinants of susceptibility may be different in
in some groups of people but not in others. This phenomenon may be due
to the variation of genetic factors that affects the susceptibility to vaccine
different populations [6]. With current technological
adverse events. In this study, we introduce the development of an Ontology advances and new biostatistics approaches to understanding
of Genetic Susceptibility Factor (OGSF) that is aligned with the Basic a large number of databases of information, we can now
Formal Ontology (BFO). OGSF represents the genetic susceptibility, better understand how genetic variations become critical to
genetic susceptibility factors and vaccine adverse events using formal
ontologies. Two case studies were used to test and validate the model. One
vaccine-induced positive host responses and adverse
case study represents a human gene allele DBR1*15:01 as a genetic reactions.
susceptibility factor to vaccine Pandemrix related multiple sclerosis. An Ontology of Genetic Susceptibility Factor (OGSF)
Genetic polymorphisms associated with smallpox vaccine adverse event was previously developed for our formalization of the
was analysed as the second use case. A SPARQL query, visualization of
extracted data as a network and the social network analysis of the network,
definitions of ‘genetic susceptibility’ and ‘genetic
further provide insights on the evaluation and application of the ontology. susceptibility factor’ using the TCF7L2 gene and its
susceptibility to Type 2 Diabetes as an example [7]. The
1 INTRODUCTION entities important for the representation of genetic
susceptibility to diseases include: genetic polymorphism,
Vaccines have enabled tremendous decreases in infectious
the population and geographical location, the disease
diseases and remain among the most effective of our public
entities, and related statistical entities (e.g., odds ratio and p-
health initiatives. At the same time, as an ever increasing
value). Here we consider that a vaccine adverse event is a
number of vaccines is administered globally, many vaccine-
pathological bodily process, and we extend the former work
associated adverse events and reactions have been identified
to model the genetic susceptibility to adverse event.
and threaten the public health successes attributable to
Based on previous studies, we have now developed a new
vaccines [1]. As defined in the Vaccine Adverse Event
version of genetic susceptibility-focused ontology, the
Reporting System (VAERS) and Ontology for Adverse
Ontology of Genetic Susceptibility Factor (OGSF) by using
Event (OAE), a vaccine adverse event is an adverse event
Basic Formal Ontology (BFO) 2.0 as its upper ontology.
following vaccination and does not assume a causal
OGSF is used to study the susceptibility factors associated
association [2]. Vaccine-related adverse events often occur
with vaccine adverse events.
in some populations but not in others, which has led to the
hypothesis of genetic susceptibility to vaccine adverse
events [3, 4]. 2 METHODS
Genetic susceptibility, also called genetic predisposition, 2.1 Ontology editing
is an increased likelihood or chance of developing a The format of OGSF ontology is W3C standard Web
particular disease due to the presence of one or more gene
Ontology Language (OWL2) (http://www.w3.org/TR/owl-
mutations and/or a family history that indicates an increased
guide/). For this study, many new terms and logical
risk of the disease. The allele that confers the increased
definition were added into original OGSF [7] using the
risk/susceptibility may be inherited but the disease itself will
not. The single locus genotype is usually insufficient to Protégé 4.3.0 build 304 OWL ontology editor
cause a disease. For the disease to appear, impaired (http://protege.stanford.edu/).
expressions of alleles at other gene loci and/or 2.2 Ontology term reuse and new term generation
environmental factors are often needed [5]. OGSF imports the whole set of the Basic Formal
Genetic susceptibility factors are the genetic entities, most
Ontology (BFO) [8]. To support ontology interoperability,
likely genetic variations, which influence the susceptibility.
many terms from reliable ontologies are reused. For this
The genetic susceptibility factors contributing susceptibility
purpose, OntoFox [9] was applied for extracting individual
to a disease may not be obvious mutations. It is more likely
a combination of subtle changes on several genes, which terms from external ontologies. For those genetic
susceptibility-specific terms, we generated new OGSF IDs
with the prefix of “OGSF_” followed by seven-digit auto-
*
To whom correspondence should be addressed: incremental digital numbers.
yuln@med.umich.edu
1
Ontology modeling of genetic susceptibility to adverse events following vaccination
2.3 Evaluation of OGSF studies, and population-based studies are conducted in order
Use case studies were designed based on literature survey. to determine whether or not a genetic variation mediates the
SPARQL was performed using the SPARQLquery plug-in diseases outcome such as a vaccine adverse event.
embedded with Protégé4.3.0 build 304. Graphed data was Fig. 1 shows how we use OGSF terms and BFO relations
extracted using the OntoGraf plug-in [10] Gephi 0.8.2 beta to represent genetic susceptibility to vaccine adverse event.
(http://gephi.org)[11] was used to conduct social network
data analysis and visualization based on the extracted graph textual conclusion of
genetic susceptibility
has_specified_output
genetic association
investigation
data from instances of OGSF. is_about
has participant at some time
2.4 Availability and access has genetic
genetic
The website for OGSF project is available at susceptibility
material
basis
susceptibility
factor
case group
http://code.google.com/p/ogsf/. The source of the ontology is_about is_a
genetic susceptibility to
is also available in the NCBO Bioportal: vaccine adverse event part of continuant has member part
at some time
at some time
http://bioportal.bioontology.org/ontologies/3214.
realized in
human vaccinee carrying
vaccine
3 RESULTS adverse event
actively participates in susceptibility allele for
adverse event
3.1 OGSF is aligned with BFO is_preceded_by inverse ('vaccine immunization for host')
The development of OGSF follows the OBO Foundry vaccination is specified input of vaccine
principles, including openness, collaboration, and use of a Fig. 1. Design pattern for representing genetic susceptibility to a
common shared syntax [12]. The early version of OGSF vaccine adverse event (VAE).
was not well aligned with BFO. To align OGSF with BFO The set of core terms representing the whole topic are
2.0 Graz version, we started with key terms and render them ‘genetic susceptibility factor’, ‘genetic susceptibility’,
using BFO's terms as parent terms. ‘adverse event’ and ‘textual conclusion of genetic
There are two core terms in OGSF: 'genetic susceptibility’. In Fig.1, the 'genetic susceptibility factor' is
susceptibility' and 'genetic susceptibility factor'. The OGSF the material basis of 'genetic susceptibility', which has a
term 'genetic susceptibility' (OGSF_0000000) is a subclass subclass ‘genetic susceptibility to vaccine adverse event’.
of 'disposition' (BFO_0000016). The alternative term for The genetic susceptibility is realized in the process of
'genetic susceptibility' is 'genetic predisposition'. Note that ‘vaccine adverse event’. The ‘genetic susceptibility factor’
in BFO 2.0 the term 'predisposition' is not included, so we is the part of a 'human vaccinee carrying susceptibility allele
put genetic susceptibility directly as the child term of for adverse event’, which ‘actively participates in’ the
'disposition'. The first level child terms of 'genetic ‘vaccine adverse event’. On the other hand, a ‘genetic
susceptibility' include: 'genetic predisposition to disease of association investigation’ has participant ‘case group’ with
type X' (OGMS_0000033), 'genetic susceptibility to the ‘human vaccine carrying susceptibility allele for adverse
pathological bodily process' (OGSF_0000001), and 'genetic event’ as its member. The ‘genetic association investigation’
susceptibility to biological process' (OGSF_0000002). The has ‘textual conclusion of genetic susceptibility’ as its
term that reveals our use case is 'genetic susceptibility to specified output, and the conclusion ‘is about’ both ‘genetic
adverse event following vaccination' (OGSF_0000010) and susceptibility factor’ and ‘vaccine adverse event’. An
it is the third level child term of 'genetic susceptibility'. inverse of VO relation: ‘vaccine immunization for host’
Another core OGSF term 'genetic susceptibility factor' interlinks the human vaccinee and ‘vaccine’. ‘Vaccine’ is a
(OGSF_0000004) is a subclass of 'material entity' specified input of the process of ‘vaccination’. Relation ‘is
(BFO_0000040). An allele, gene, genotype, and haplotype preceded by’ linking ‘vaccination’ and vaccine adverse
can be genetic susceptibility factors. The relation: 'material event’ indicates that ‘vaccination’ happens before the
basis of at some time' (BFO_0000127), is used to link ‘vaccine adverse event’.
genetic susceptibility factor and genetic susceptibility.
3.3 Modeling genetic association study
3.2 Modeling genetic susceptibility to adverse event Studies have provided many supporting evidences for
following vaccination asserting susceptibility factors to adverse event outcomes.
The genetic susceptibility to vaccine adverse events is used Based on the OBI framework, we specially modeled the
as a use case for OGSF redesign. genetic association study designs according to our use case.
Genetic susceptibility reflects the relation between a The textual definition of OGSF term 'genetic association
genetic factor (e.g. allele) and risk of condition, disease or investigation' was given as: 'an investigation that aims to
responses to vaccines or drugs. Different levels of genetic test whether single-locus alleles or genotype frequencies (or
association studies, such as family studies, genetic linkage more generally, multilocus haplotype frequencies) differ
2
Ontology modeling of genetic susceptibility to adverse events following vaccination
between two groups of individuals (usually diseased Vrethem et al. reported the occurrence of severe
subjects and healthy controls)'. Different types of those narcolepsy with cataplexy and multiple sclerosis (MS) in a
studies exist, such as 'case-control study', 'GWAS study' previously healthy young male in association with
(Genome-Wide Association Study) and 'case report'. Pandemrix vaccination [14]. The investigators found that
'GWAS study' is a type of 'case-control study' and has two that those patients carrying HLA allele DBR1*15:01 were
subclasses 'initial GWAS study' and 'replicate GWAS associated with MS and those having HLA allele
study'. The statistical method conducted in a study is DQB1*06:02 were associated with narcolepsy. It was also
modeled as 'data analysis' that is a part of an investigation as concluded that the genetic susceptibility in this patient is a
asserted in OBI. 'Case group' and 'control group' are clue that an immune-mediated mechanism and a common
subclasses of 'human study subject group'. The 'human study etiology for both diseases in this patient.
subject group' is the participant of the 'genetic association The DBR1*15:01 as a genetic susceptibility factor
investigation'. responsible for Pandemrix-induced MS was modeled in the
A statistical analysis of the genetic susceptibility is based class level using OGSF, and the particular study was
on the choice of a statistical study design, which depends on modeled in instance level using OGSF (Fig 2).
several factors related to the phenotype: the population, the At the class level, 'DBR1*15:01' is an 'allele of HLA
accurate measurement of environmental factors, and known gene', which is also the material basis of (BFO 2: 'material
genetic background among other factors. Due to the basis of at some time') 'genetic susceptibility to vaccine
presence of many different cofounders, it is often difficult to adverse event'. The instance of ‘DBR1*15:01’ is a part of
detect and verify genetic susceptibility factors associated the MS patient instance. In class level, 'multiple sclerosis
with specific adverse event outcomes. Observed statistically AE patient' 'actively participates in' the 'multiple sclerosis
significant genetic susceptibilities may be contradictory AE' process. Multiple Sclerosis adverse event is preceded
among different studies [13]. More and consistent by the 'Pandemrix vaccination'. 'Pandemrix' is a participant
observations in different populations may give stronger of 'Pandemrix vaccination' and it is related to the MS patient
evidence to support the true causal relation between a using a short relation from Vaccine Ontology (VO): 'vaccine
'genetic susceptibility factor' and an observed outcome. immunization for host', which relates a vaccine with a
Well-designed experiments may be applied to verify the vaccinee.
association. In order to store the result from genetic
association studies, we use 'textual conclusion of genetic publication_PMID case only study
_22841884
susceptibility' to be asserted as 'specified output of' a is_about instance of
'genetic association investigation'. The 'textual conclusion
positive conclusion of genetic association
of genetic susceptibility' is a 'textual entity'. The 'is about' genetic susceptibility_1
has specified output
study_1
relation was used to link the conclusion with 1) 'genetic genetic susceptibility to
susceptibility factor' and 2) ‘vaccine adverse event’ process. is_about
vaccine adverse event
material basis of at some time
Three terms: 'positive conclusion of genetic is_about
is allele HLA DRB1 has participant
susceptibility', 'negative conclusion of genetic susceptibility' is_about DRB1*15:01 of gene gene at all times
instance of
and 'neutral conclusion of genetic susceptibility' are asserted
DRB1*15:01 (instance) 'part of continuant
as subclasses of 'textual conclusion of genetic susceptibility'. at all times
that whole exists'
A 'positive conclusion of genetic susceptibility' means that a multiple actively multiple sclerosis instance multiple sclerosis AE
positive conclusion is drawn based on a significant sclerosis AE participates in AE patient of patient_1
statistical association of a genetic factor and a vaccine is preceded by
inverse ('vaccine immunization for host')
adverse event as studied in this paper. A 'negative Pandemrix participates in
Pandemrix
vaccination at some time
conclusion of genetic susceptibility' a denied association
between a genetic factor and an adverse event. Sometimes, Fig. 2. OGSF modeling of vaccine-associated multiple sclerosis
depending on the data, an investigator may draw a
conclusion of a non-significant association but without a Since it is a case report, this study gives one specific
clear deny of a possible association. This situation is positive supporting evidence to the genetic susceptibility of
captured using ‘neutral conclusion of genetic susceptibility’. DBR1*15:01, which is asserted at the instance level. We use
'genetic association study_1' to represent the study, which
3.4 Case study gives a specific output 'positive conclusion of genetic
Case studies are used for two purposes: 1) to validate the susceptibility_1'. This specific conclusion is about the entity
modeling, 2) to test possible applications of the ontology. 'DBR1*15:01' and the 'multiple sclerosis AE'.
3.4.1 Case study 1: HLA allele DBR1*15:01 is genetic 3.4.2 Case study 2: genetic polymorphisms associated with
susceptibility to Pandemrix related multiple sclerosis adverse events after smallpox vaccination
3
Ontology modeling of genetic susceptibility to adverse events following vaccination
Reif et al. reported that genetic polymorphisms in an The instance level representation representing two
enzyme methylenetetrahydrofolate reductase (MTHFR) and independent studies provide the statistical supporting
an immunological transcription factor (IRF1) were evidence to the genetic susceptibility (Fig. 3).
associated with AEs after smallpox vaccination [15]. In this Fig 3 illustrated that two ‘positive conclusions of genetic
study, two independent clinical trials were conducted as susceptibility’ from clinical trail 1 and trail 2 support the ‘T
initial and replicating genetic association studies separately. allele of rs1801133 SNP’ as the ‘material basis of at some
The Odds Ratio was used to measure the association time’ the ‘genetic susceptibility of adverse event following
between genotypes and systematic adverse event. Only vaccination’. The datatype properties ‘hasOddsRatio’ and
strong association supported by a statistically significant ‘hasPvalue’ are properties of the ‘positive conclusion of the
Odds Ratio in both studies was considered and asserted as a genetic susceptibility’. Using these datatype properties, the
true positive genetic association. real data denotes the statistical power was represented in the
In this case, the important information to be stored is the ontology.
susceptibility allele of the SNPs and the statistical power in positive conclusion of genetic adverse event
hasOddsRatio genetic
two studies. Those information was curated and summarized hasPvalue susceptibility_trail2
has specified output association clinical
trail_2
in Table 1. hasSize
participates
Table 1. Statistical summary of genetic susceptibility factors with is about is about case group
at all times
is about
systematic adverse event following smallpox vaccination in trail2
genetic material systematic adverse
T allele of
GSF& Allele Gene Odds Ratio P-value Study susceptibility basis of
rs1801133 event after smallpox
publication_PMID
_18454680
of vaccine at some
vaccination
SNP
1 or 2 adverse event time
case group
rs1801133 SNP T MTHFR 2.3 (1.1–5.2) 0.04 1 is about in trail1 participates
is about
is about
at all times
rs1801133 SNP T MTHFR 4.1 (1.4–11.4) 0.01 2 hasSize
positive conclusion of genetic adverse event
rs9282763 SNP G IRF1 3.2 (1.1–9.8) 0.03 1 hasOddsRatio genetic has specified output association clinical
hasPvalue susceptibility_trail1 trail_1
rs9282763 SNP G IRF1 3.0 (1.1–8.3) 0.03 2
rs839 SNP A IRF1 3.2 (1.1–9.8) 0.03 1 Fig. 3. Modeling Case Study 2 using OGSF
rs839 SNP A IRF1 3.0 (1.1–8.3) 0.03 2
Haplotype 1* G,A IRF1 3.2 (1.0–10.2) 0.03 1 3.4.3 SPARQL query
Haplotype 1* G,A IRF1 3.0 (1.0–9.0) 0.03 2 A SPARQL script was developed to query against inferred
Haplotype 2# T,C,A IL4 2.4 (1.0–5.7) 0.05 1 OGSF ontology. The query led to the retrieval of the genetic
Haplotype 2# T,C,A IL4 3.8 (1.0–14.4) 0.06 2 susceptibility factors, as shown in Table 1. (Sparql query
Notes: script shown in Supplemental material if allowed).
& GSF stands for Genetic Susceptibility Factor
* Haplotype 1 contains G allele of rs9282763, A allele of rs839 in IRF1 gene.
# Haplotype 2 contains T allele of rs2070874,C allele of rs2243268, A allele of 3.4.4 Visualization and social network analysis
rs2243290 in IL4 gene. In order to give a better view of the terms and links between
The class level assertion is similar to case study 1. For terms, data from case study 2 was extracted using OntoGraf
example, the constrains representing one of the genetic and visualized using Gephi as following (Fig. 4 and 5).
susceptibility factors, A allele of rs839, are as follows:
1. 'material basis of at some time' some 'genetic susceptibility to
adverse event following vaccination'
This axiom denotes that the A allele of rs839 is the material basis
of the genetic susceptibility to AE induced by vaccination
2. 'part of continuant at all times that whole exists' some ('human
vaccinee experiencing systemic adverse event' and inverse('vaccine
immunization for host') some 'Smallpox virus vaccine')
This axiom denotes that the ‘A allele of rs839’ is part of some
human who is experiencing systemic adverse event and had
vaccinated by Smallpox vaccine
3. isContainedIn some 'IRF1 gene'
This axiom denotes that the ‘A allele of rs839’ is contained in IRF1
gene
4. 'alternative allele of SNP'
This axiom denotes that the ‘A allele of rs839’ is an alternative
allele
5. 'susceptibility allele' (inferred) Fig. 4. All related nodes within case study 2.
This axiom denotes that the ‘A allele of rs839’ is a susceptibility
allele, so it is a genetic susceptibility factor. Fig. 4. shows how the data and terms interlinked with
each other in the network of case study2. The most
4
Ontology modeling of genetic susceptibility to adverse events following vaccination
connected node is ‘systematic adverse event after smallpox with the same adverse event C. To add this fact into OGSF
vaccine’, since there are 10 conclusions related to it as would strengthen the belief that gene G is related to the
shown in table1. All the genes, relevant SNP alleles and genetic causal association.
haplotypes are interlinked with each other, and can be The notion of genetic susceptibility can be expressed
captured as a community within the network, which using OWL classes, whereas each study is modeled in
indicated by colors of the node. instance level as data item. To simplify the connections, the
Running Gephi’s ‘filter’ function, two different views of relation 'is_about' was used to bridge the individual level
the network of case study 2 were yield as shown in Fig 5. 'textual' conclusions from an individual study to a 'genetic
susceptibility factor' (class level) and specific vaccine
adverse event (class level). The efficiency and applicable
Fig. 5. Two views of the aspects of these relations need to be tested using more
genetic susceptibility complicated datasets and SPARQL query.
network in case study2.
4.2 The granularity of genetic susceptibility factor is
(A). EgoNetwork filter
at allele level
view of the network,
which shows entities that
Nowadays, thousands of Single Nucleotide polymorphisms
are directly linked to
(SNPs) can be tested efficiently in large population-based
'genetic susceptibility to
studies. Researchers are using various entities to describe
vaccine adverse event'.
genetic susceptibility bearers, such as genotype, SNP, LD
(B) Closeness centrality
block, haplotype and so on. Except for LD block, other
filtered view of the
genetic susceptibility factors can be represented by notion of
network. All the dots in
allele. As defined in our previously developed Ontology for
the figure have closeness
Genetic Interval (OGI) [16], ‘allele’ is ‘an alternative form
centrality value equal to
of a genetic interval that is located at a specific position on a
0.
specific chromosome’. In OGI, term 'allele' has following
subclasses: 'allele of gene', 'allele of polymorphism', 'allele
of SNP', 'allele of phenotype', 'allele shared by sibs'. OGSF
fully imports OGI, thus inherited the OGI's allele classes
Combining Fig. 5A and 5B, it indicates that: 1) in OGSF, and definitions. OGI gives formalized topological relations
the genetic susceptibility is directly related with variants, between alleles and genes, so that the relations between
such as SNPs and haplotypes. 2) Gene is indirectly linked to alleles and genes can be logically calculated [14]. Adopting
genetic susceptibility via variants. The in-directed those relations ensure the example discussed in the section
connection can be captured by centrality network analysis in 4.1 can be reasoned in OGSF.
the given data set. In our specific case study 2, the closeness 4.3 Visualization of sub network of OGSF data
centrality calculations of genetic susceptibility, adverse The ontology's instance level data can be visualized as
event and genes are the lowest. directed graph. The visualization and network analysis
results provide deep insights in terms of ontology designing.
4 DISCUSSION Representing the genetic susceptibility can be addressed
4.1 Representing genetic susceptibility requires the using three layers of information depending on researchers'
notion of instance level evidence interest. The first layer is the direct link of types of genetic
The purpose of representing the knowledge of genetic factors and investigated adverse event. In our representation,
susceptibility here is to extend existing beliefs by adding it is grounded to allelic variant level. The second layer is
new facts. For example, if in one study A1, the genetic the supporting conclusion that provides positive evidence to
factor SNP B is statistically significant related to an adverse the direct link. The third layer is the linking between a gene
event C, then the SNP B as a genetic susceptibility factor and the investigated adverse event. Since in OGSF, gene
will be represented using the OGSF framework. This and adverse event are not directly linked, the social network
knowledge will become an existing belief, when another analyses shows that this indirect link can be measured
study A2 reached the same conclusion, this fact will be mathematically and thus provide the foundation for
added into the OGSF knowledgebase and hence provide prediction. It is noted that usually only significant
stronger supporting evidence to the genetic causal associations were reported in the literature, and many
association. Another example is that suppose gene G is negative results may not be available. The network analysis
related with both SNP B and SNP E, when another study A3 may be biased.
gave the conclusion of SNP E statistically significant related
5
Ontology modeling of genetic susceptibility to adverse events following vaccination
In conclusion, based on the formalization of genetic 8. Grenon P: Spatio-temporality in Basic Formal
susceptibility, OGSF provides a frame work to represent the Ontology. In: IFOMIS reports. Edited by Grenon
genetic allelic variants, genes and pathological processes. It P. Leipzig: 2003: 89.
requires ontological scientific discourse representations as 9. Xiang Z, Courtot M, Brinkman RR, Ruttenberg A,
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ACKNOWLEDGEMENTS biomedical data integration. Nat Biotechnol
This project was supported by a NIH-NIAID grant 2007, 25(11):1251-1255.
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