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Salivaomics
David T.W. Wong
JADA 2012;143(suppl 10):19S-24S
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Salivaomics
David T.W. Wong, DMD, DMSc
he science of saliva has
T advanced substantially in the
past decade. Both basic and
translational sciences have
progressed as a result of the balanced
portfolio of research invested in by
the National Institute of Dental and
Craniofacial Research (NIDCR),
Bethesda, Md. Much of this support
was designated for the ambitious,
visionary campaign to decipher and
catalog the human salivary proteome
and to apply that knowledge to the
development of saliva-based point-of-
care technologies. After a decade of
scientific advancements, the incipient
maturation of these basic and trans-
lational outcomes is leading to the
development of clinical tests that ben-
efit patients. In this article, I present
the current status of saliva-based
innovation and its application to the
detection of oral and systemic
diseases.
It is important to define a few
ideas and terms. The first is the term
“salivary diagnostics,” which has
become a catchall for the entire field
of salivary science. Although we
expect that clinicians eventually will
use saliva to detect diseases, this
application is not the most com-
pelling at this time. As of March
2012, no salivary test exists to diag-
nose a single oral or systemic disease.
Not even the U.S. Food and Drug
Administration (FDA)–approved
OraQuick ADVANCE Rapid HIV-1/2
Antibody Test (OraSure Technologies,
Bethlehem, Pa.) is diagnostic for
human immunodeficiency virus
(HIV) infection; it claims only to
Copyright © 2012 American Dental Association. All rights reserved.
AB STRACT
Background. The ability to monitor health and wellness, as well
as detect oral and systemic illnesses early through noninvasive
means, are highly desirable goals in health care promotion and
delivery. Saliva is an emerging medium to be explored for health
and disease surveillance, as well as for personalized medicine. A
major mandate is to demonstrate clinicians’ ability to use saliva to
detect and monitor systemic diseases.
Methods. To realize the translational and clinical vision of sali-
vary diagnostics, two prerequisites are essential. The first is the
need to develop and optimize diagnostic tools tailored to saliva. The
second is the need to substantiate the scientific underpinnings of
salivary biomarkers reflecting systemic diseases.
Results. The author describes five diagnostic alphabets (pro-
teome, transcriptome, microRNA, metabolome and microbiome)
and point-of-care technology platforms that are in place to advance
the translational and clinical path. For mechanistic studies (that is,
basic science studies), animal models are in place to elucidate the
scientific mechanisms of systemic diseases reflected in saliva.
Conclusions. Significant advancements have been made in the
development of salivary diagnostic tools. The translation of the sci-
entific mechanisms of systemic diseases reflected in saliva is in
progress.
Clinical Implications. On the scientific credentialing of sali-
vary biomarkers for the detection of systemic diseases, salivary
diagnostics will have an effect on access to care, health disparities
and global health. Dentistry can advance into the realm of primary
health care with integration of chairside screening for medical
conditions.
Key Words. Saliva; biomarkers; proteome; transcriptome;
metabolome; microbiome; early detection; systemic diseases; point-
of-care technology; personalized medicine.
JADA 2012;143(10 suppl):19S-24S.
Dr. Wong is the Felix and Mildred Yip Endowed Professor, associate dean of research and
director, Dental Research Institute, University of California, Los Angeles (UCLA), School of Den-
tistry; professor, School of Engineering, UCLA; professor, Division of Head and Neck Surgery-
Otolaryngology, David Geffen School of Medicine at UCLA; member, Jonsson Comprehensive
Cancer Center, UCLA; and member, Molecular Biology Institute, UCLA. Address reprint requests
to Dr. Wong, UCLA School of Dentistry, 73-017 CHS, 10833 Le Conte Ave., Los Angeles, Calif.
90095, e-mail dtww@ucla.edu.
JADA 143(10 suppl) http://jada.ada.org October 2012 19S
 Downloaded from jada.ada.org on September 3, 2014
screen for the presence of antibodies to HIV-1 in
saliva. These antibodies suggest HIV-1 infection,
but the assay is not robust enough to prove it. A
confirmatory test (OraSure HIV-1 Western Blot,
OraSure Technologies) is required to actually
diagnose HIV-1 infection. The two tests are
designed to work together, with a rapid, conven-
ient and inexpensive saliva-based screening step
followed by a validated, accurate, laboratory-
based Western-blot assay for confirmation. Saliva
and its constituents, together with the test’s non-
invasiveness, make it better suited for disease
screening and risk assessment than for diagnostic
purposes.
However, tests are available that confirm the
presence of infection on the basis of salivary
samples (for example, MyPerioPath, OralDNA
Labs, Brentwood, Tenn.).
Neither the translational potential nor the
soluble constituents of saliva, blood and other
bodily fluids are identical. In terms of commer-
cializing a new molecular-diagnostic product,
they could be mutually exclusive. The infrastruc-
ture of clinical laboratories and blood-serum
detection assays are so well developed that there
is no need for replacement. However, the early
detection and diagnosis of cancer, for example,
through the development of biomarkers in blood,
urine and other bodily fluids have not been
forthcoming. The lack of commercial success of
serum-based markers represents an opportunity
for salivary diagnostics. Indeed, several salivary
biomarkers for oral and systemic diseases are
poised for translational and clinical applications.
SALIVAOMICS
The term “salivaomics” was coined in 2008 to
reflect the rapid development of knowledge
about the various “omics” constituents of saliva1
(that is, the study of related sets of biological
molecules). In only five years, the terms “sali-
vary proteome,” “transcriptome,” “microRNA”
(miRNA), “metabolome” and “microbiome” have
entered the scientific lexicon. The metabolome
is the complete set of small molecular metabo-
lites found within a biological sample (including
metabolic intermediates in carbohydrate, lipid,
amino acid, nucleic acid and other biochemical
pathways, along with hormones and other sig-
naling molecules). These are the diagnostic
alphabets of saliva, and their discovery has
positioned saliva for translational and clinical
applications, including personalized medicine
and dentistry.
Investigators discovered the salivary transcrip-
tome in 20042,3; it consists of a core of 180 mes-
senger RNAs (mRNAs). The core salivary pro-
20S JADA 143(10 suppl) http://jada.ada.org October 2012
Copyright © 2012 American Dental Association. All rights reserved.
teome contains 1,166 proteins, as determined by
the collective efforts of three NIDCR-supported
groups, including my research group at Univer-
sity of California, Los Angeles (UCLA).4,5 The
UCLA research group, together with the research
group headed by Masaru Tomita, PhD, at Keio
University, Tsuruoka City, Yamagata, Japan,
deciphered the salivary metabolome and demon-
strated its utility for detection of oral and sys-
temic diseases.6
Farrell and colleagues7 recently showed that
the potential for variation in the salivary micro-
biome could be used in the detection of early
resectable pancreatic cancer. Two microbial
markers (Neisseria elongata and Streptococcus
mitis) yielded a receiver operating characteristic
plot area under the curve value of 0.90 (95 per-
cent confidence interval, 0.78-0.96; P < .001),
with a 96.4 percent sensitivity and an 82.1 per-
cent specificity in distinguishing patients with
early-stage resectable pancreatic cancer from
study participants who did not have cancer.7
Area under the curve is a measure of the ability
of a test to accurately discriminate a result indi-
cating a particular disease state from a result
not indicating that disease state.
SALIVARY BIOMARKER DEVELOPMENT
The rapid substantiation of salivaomic con-
stituents has enabled researchers to discover,
develop and validate biomarkers for early detec-
tion of disease, treatment monitoring, recurrence
prediction and other translational and prognostic
outcome assessments. The availability of the five
diagnostic alphabets—proteins, mRNAs,
miRNAs, metabolic compounds and microbes—
offers substantial advantages because disease
states may be accompanied by detectable
changes in one, but not all, dimensions. Investi-
gators have developed informatics and statistical
tools to determine the most discriminatory com-
bination of salivary biomarkers for specific oral
and systemic diseases (Figure 1).8
The combination of power and flexibility rep-
resents the true value of salivary biomarkers.
Researchers can develop new biomarkers for
ABBREVIATION KEY. CLIA: Clinical Laboratory
Improvement Amendments. FDA: Food and Drug
Administration. HIV: Human immunodeficiency
virus. LDT: Laboratory-developed test. mRNA: Mes-
senger RNA. miRNA: MicroRNA. NIDCR: National
Institute of Dental and Craniofacial Research. PBS:
Phosphate-buffered saline. POCT: Point-of-care tech-
nology. PRoBe: Prospective-specimen-collection,
retrospective-blinded-evaluation. SALO: Saliva
ontology. SKB: Salivaomics Knowledge Base. UCLA:
University of California, Los Angeles.
 Downloaded from jada.ada.org on September 3, 2014
disease detection directly in saliva. No longer do
we need to conduct “me-too” research that relies
on biomarkers found first in blood or in other
fluids. Researchers now can develop salivary
biomarkers for early detection of diseases by
using inherent omics constituents, prospective
study designs,9 saliva-based bioinformatics and
statistical tools.
THE SALIVAOMICS KNOWLEDGE BASE
Omics are scientific disciplines constituting the
study of related sets of biological molecules.
Examples include genomics, transcriptomics,
proteomics, metabolomics and epigenomics.
Among other purposes, the science of omics is
enabling the emerging discipline of personalized
medicine and development of omics-based tests.
Omics-based tests are assays composed of or
derived from many molecular measurements,
and the findings are interpreted by a fully speci-
fied computational model to produce a clinically
actionable result.
A vast amount of salivaomics data has been
generated with the use of high-throughput tech-
nologies.10-13 However, researchers still encounter
barriers in seeking to exploit such data, including
a lack of computationally accessible salivary data
and an inability to cross-reference data sets from
different types of studies. The need to overcome
these barriers led the researchers at UCLA to
develop the Salivaomics Knowledge Base (SKB), a
data management system and Web resource that
supports salivary diagnostics research.8 The SKB
facilitates use of salivary data in several ways.
The research team at UCLA is building it on the
basis of the saliva ontology (SALO) and SDxMart
(defined below), which allow the SKB to operate
with other omics databases as part of a general
strategy to facilitate integration of heterogeneous
and disparate data sources in a systems biology
approach. To my knowledge, SALO and SDxMart
are the first of their kind in dentistry.
Saliva ontology. The SALO is a detailed
ontology of saliva that is optimized to meet the
needs of both the clinical diagnostic community
and the cross-disciplinary community of omics
researchers.14 Ontologies are controlled, struc-
tured vocabularies designed to provide a
consensus-based means of ensuring consistent
description of data by scientists working in dis-
parate domains. As applied in the biomedical
domain, ontology plays a key role in promoting
consistent annotation of biological and medical
information. The SALO shares a framework
with the well-established gene ontology effort15
and with other disciplinary ontologies within
the Open Biomedical Ontologies Foundry
JADA 143(10 suppl)
Copyright © 2012 American Dental Association. All rights reserved.
Oral and Systemic Diseases
1. Biomarker Discovery
Proteome Transcriptome MicroRNA Metabolome Microbiome
2. Preclinical Validation
3. Definitive Academic Validation (PRoBE Design)
4. FDA Pivotal Validation, Multicenter, PRoBE Design
Figure 1. Biomarker development and roadmap for approval by
the U.S. Food and Drug Administration (FDA). PRoBe: Prospective-
specimen-collection, retrospective-blinded-evaluation.
(http://obofoundry.org). The SALO is created
through cross-disciplinary interaction among
saliva experts, protein experts, diagnosticians
and ontologists.14
BioMart. BioMart is a free, open-source data-
base system.16,17 It is cross-platform and supports
many popular relational database management
systems, including MySQL (Oracle, Redwood
Shores, Calif.), PostgreSQL (PostgreSQL Global
Development Group), SQL Server (Microsoft,
Redmond, Wash.) and DB2 (IBM, Armonk, N.Y.).
The software is database agnostic; therefore, it
can be adapted easily to existing data sets. It is
expandable and customizable through a plug-in
system; because it is open source, the general
community can participate in its development.
Furthermore, BioMart seamlessly can connect
databases that are geographically disparate,
facilitating collaboration between groups.
All of these features have catalyzed the cre-
ation of BioMart Central Portal18,19 a first-of-its-
kind community-supported effort to create a
single access point integrating many inde-
pendent databases. Anyone can contribute an
independently maintained resource to the cen-
tral portal, allowing it to be exposed to, and
shared with, the research community, as well as
linking it with other resources in the portal.
Users can take advantage of the common inter-
face to quickly access different sources of infor-
mation without learning a new system for each.
The system also simplifies cross-database
searches that otherwise might require several
complicated steps. Several integrated tools
streamline common tasks such as converting
between identification formats and retrieving
sequences. The combination of a wide variety of
databases, an easy-to-use interface, robust pro-
gram access and an array of tools make BioMart
http://jada.ada.org October 2012 21S
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Figure 2. Rodent model identifying and unraveling mechanisms of salivary diagnostics for systemic diseases. Lung cancer and
melanoma tumors are induced in rodents and allowed to develop fully (A). Tumors, blood, saliva and salivary glands are harvested and
biomarkers are examined by using high-throughput technologies such as expression microarrays (B). Statistical results and bioinfor-
matics are used to identify biomarkers that are differentially present only in saliva of tumor-bearing animals (C). Researchers then
develop working models and hypotheses to address the mechanistic pathways of distal disease development and onset of salivary bio-
markers that reflect the distal diseases (D). PBS: Phosphate-buffered saline. Adapted from Gao and colleagues.21

Central Portal a one-stop source of biological SALIVARY DIAGNOSTICS FOR SYSTEMIC

data.18,19
SDxMart. The SDxMart is a BioMart data
portal that hosts salivary proteomic, transcrip-
tomic, metabolomic and miRNA data and offers
access to the data via use of the BioMart inter-
face and querying environment. The SDxMart is
designed to enable users to make a variety of
queries—including complex queries that inte-
grate genomic, clinical and functional informa-
tion—to facilitate salivary biomarker discovery.
The SDxMart contains data from studies of
oral diseases and systemic diseases, including
oral cancer, Sjögren syndrome, pancreatic cancer
and breast cancer. The portal indexes proteomic,
transcriptomic, miRNA and metabolomic data
sources. In addition, the SDxMart integrates
several public databases, including the Ensembl
genome database (Ensembl release 37, Ensembl,
a joint project of European Bioinformatics Insti-
tute and Wellcome Trust Sanger Institute,
Hinxton, England).20 The number of associated
resources is growing continuously.
DISEASES
Although saliva as a proximal biofluid in the oral
cavity is intuitively sound for detection of oral
diseases (that is, periodontal disease, caries, oral
cancer, salivary gland disorders), its use for
nonoral distal diseases remains largely specula-
tive. The lack of a clear mechanism showing how
salivary biomarkers can reflect disease states
elsewhere in the body has hampered the scien-
tific acceptance of this emerging field. Animal
models are the best tools to bridge this credi-
bility gap, and investigators in several studies
have used rodent tumor models to examine the
connection between nonoral cancers and salivary
biomarkers (Figure 221). A working hypothesis
currently being tested is that tumor-shed
microvesicular structures known as exosomes
(30-100 nanometers in size) can shuttle tumor-
specific contents to different parts of the body
including the salivary glands, leading to the
appearance of disease-discriminatory markers in
saliva.22 I envision that the eventual discovery

22S JADA 143(10 suppl) http://jada.ada.org October 2012

Copyright © 2012 American Dental Association. All rights reserved.
 Downloaded from jada.ada.org on September 3, 2014

and acceptance of a scientific mechanism Salivary Diagnostics

underpinning the validity of salivary
diagnostics will credential salivary bio- Diseases
markers for translational and clinical
applications. Oral POCT Systemic
Although the mechanistic underpin- (SDxMart Portal)

ning awaits validation, translational and Salivary Biomarker Salivary Biomarker Scientific Mechanism
clinical research into salivary bio- Development Development

markers has been conducted at full

throttle for several years. Cancer detec- Discovery Discovery

tion is the most active area, with notable LDT LDT

efforts in detecting breast cancer,23 pan- (CLIA) Prevalidation
(Academic)
Prevalidation
(Academic)
(CLIA)

creatic cancer,7,24 lung cancer25 and

Product Product
ovarian cancer.26 Efforts are in place for Development Validation Validation Development
the study of existing markers for sali- (FDA) (FDA)

vary detection of myocardial infarct

Figure 3. Scientific, translational and clinical developmental pathway for
(heart attack)27,28 and of new markers salivary diagnostics. CLIA: Clinical Laboratory Improvement Amendments.
primarily for Sjögren syndrome in FDA: Food and Drug Administration. LDT: Laboratory-developed test. POCT:
patients with sicca symptoms (dry eyes, Point-of-care technology.
29-31
dry mouth). Researchers can advance
these assays through the clinical validation clinical laboratory certified by the Clinical Labo-
pathway (Figure 3), culminating in pivotal trials ratory Improvement Amendments (CLIA) pro-
and approval by the FDA. gram but have not been evaluated by the FDA.
Congress passed the CLIA to establish quality
CHAIRSIDE SCREENING FOR MEDICAL standards for laboratories to ensure the accu-
CONDITIONS IN DENTAL OFFICES racy, reliability and timeliness of patients’ test
More Americans see dentists regularly than results, regardless of where the test is
they do physicians. Greenberg and colleagues32 performed.
surveyed 1,900 practicing dentists in the United The path forward for salivary diagnostics is
States and asked them whether they would be timely and will mature into clinical uses, likely
willing to collect a sample of saliva and send it starting with oral cancer screening and risk
to a laboratory for diagnostic evaluation. assessment. For detection of oral cancer,
Eighty-seven percent of surveyed practitioners researchers have developed salivary biomarkers
responded “yes,” demonstrating how receptive by using proteomic,33 genomic,3 miRNA34 and
the dental profession is to saliva-based screens metabolomic6 technologies. Recently, the National
and risk-assessment technologies. Combined Cancer Institute’s Early Detection Research Net-
with the fact that about 20 percent more Ameri- work independently validated proteomic and
cans visit their dentists regularly than they do genomic salivary biomarkers.35 Investigators have
their physicians and that a dentist has, on evaluated and confirmed the oral cancer salivary
average, a roster of about 2,000 patients, the 20 biomarkers in Indian36 and Serbian populations.37
percent differential between visits to dentists The salivary biomarkers for oral cancer detection
and visits to physicians translates into substan- now are ready for definitive academic validation
tial opportunities for dentists to engage in the by means of a prospective clinical study design
early detection of life-threatening conditions. (Figure 1).
When clinicians integrate salivary diagnostics The translational path for oral disease will be
fully into dentistry, it will have the potential to at a different pace from that for systemic dis-
advance the profession into primary health care. ease, largely because of the need to substantiate
the scientific rationale of salivary biomarkers
THE PATH FORWARD for systemic disease, as well as the need for
Central to the path forward for salivary diagnos- researchers in ongoing studies to determine the
tics for oral and systemic diseases is the develop- mechanisms of distal diseases reflected in sali-
ment of discriminatory, robust and validated sali- vary biomarkers (Figure 3). In addition to HIV,
vary biomarkers that eventually will advance to for which there is an FDA-approved autoanti-
the FDA for definitive validation and then to the body detection test, infectious diseases of local
product development stage. Laboratory-developed origin (caries and periodontal diseases) and sys-
tests (LDTs) are laboratory tests that have been temic origin (human papillomavirus and hepa-
designed for patient care and are performed in a titis C virus) will be detectable in saliva.

JADA 143(10 suppl) http://jada.ada.org October 2012 23S

Copyright © 2012 American Dental Association. All rights reserved.
 Downloaded from jada.ada.org on September 3, 2014
CONCLUSIONS
We should look forward to the day when science
will confirm the clinical applications of salivary
biomarkers for systemic diseases; when research
opens up new doors for translational and clinical
applications; when payers are in place to adopt
saliva-based technologies into clinical practice;
and when investors are in place to develop the
infrastructures needed to advance salivary diag-
nostics into a clinical reality. Finally, we should
look forward to the time when dentists and
organized dentistry will embrace salivary diag-
nostics and integrate it into clinical practice, thus
advancing dentistry into primary health care. ■
Disclosure. Dr. Wong owns intellectual property related to the
salivary diagnostics field.
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