Biomarker Discovery: Study Design and Execution - Proteomic and Metabolomic Approaches to Biomarker Discovery - page 4

provide higher sensitivities and speci cities for

disease diagnosis than is afforded with a single
marker. Proteomic and metabolomics pattern
analysis relies on comparison of differences in
relative abundance of a number of polypep-
tides/proteins and metabolites (mass-to-charge
ratio [ m/z ] and intensity) within the mass spec-
trum or the nuclear magnetic resonance (NMR)
spectrum of two sample sets.

recurring nature and the three- to six-monthmoni-
toring requirements, making it a very expensive
disease to treat. It is disheartening that a lot of
effort and funds have been spent on

nding
a biomarker for bladder cancer without resulting
in an acceptable test to replace cystoscopy, voided
urine cytology, and imaging studies d the current
standards of care for the detection andmonitoring
of bladder tumors. A literature search indicates the
presence of many molecular biomarkers for
bladder cancer 3 ; however, none of the molecular
markers have proven to be sensitive and speci

Metabolomics
Metabolomics, also known as metabonomics,
is the study of a complete set of small molecules
(less than 1,500 Daltons [Da]) found within a bio-
logical system for the understanding of biolog-
ical processes in normal and disease states.
Direct quantitative measurements of metabolite
expressions in urine, serum, plasma, and tissue
are essential but extremely dif

c
enough to replace cystoscopy. 4 Another reason
why most published proteomic and metabolomic
studies have not provided results that have pro-
gressed from the laboratory to the clinic is that
the majority of studies stopped at the discovery
phase and never progressed onto the necessary
veri cation or validation phases.

The following biomarkers have been approved
by the U.S. FDA as qualitative tests for bladder
cancer: nuclear matrix protein (NMP22) with 56%
sensitivity; bladder tumor antigen (BTAstat) with
58% sensitivity; and UroVysion with 36% to 65%
sensitivity, 5 and hyaluronic acid and hyalu-
ronidase measurements have a sensitivity of
92%. 6 Although none of thesemarkers are sensitive
enough to be recommended for population
screening for bladder cancer , they might be used
to monitor the recurrence of the disease.
To get a relative understanding of these levels
of sensitivity, it is worth discussing prostate
cancer, in which the levels of circulating pros-
tate-speci

cult due to the
complexity and concentration dynamic range
of the metabolites in a biological sample. The
difference between metabolomics and metabo-
nomics is that metabolomics is the qualitative
and quantitative measurement of all metabolites
in a system, and metabonomics is the compar-
ison of metabolite levels (pro

les) found in two
different samples: healthy and diseased.

THE CURRENT STATE OF
BIOMARKER DISCOVERY

c andmedical litera-
ture clearly indicates that most protein andmetab-
olite biomarkers presently in use are inadequate to
replace an existing clinical test, or their only utility
is for detecting advanced stage cancers, for which
the survival rate is low. Many molecular
biomarkers have been suggested for the detection
of cancer and other diseases; however, none
possess the required sensitivity and speci

Examination of the scienti

c antigen (PSA) is used as a diagnostic
test. For men age 50 and older, the presence of
PSA levels

4 ng/ml may indicate the presence
of prostate cancer. The sensitivity, speci city,

and positive predictive values of PSA (86%,
33%, and 41%, respectively) are not suf

cient
for widespread acceptance of this marker as
a screening tool for prostate cancer. However,
the FDA has approved the use of the PSA test
along with a digital rectal exam. 7
Do increases in PSA levels give higher sensi-
tivity and speci

city.
The state of biomarker research may be illustrated
by using bladder cancer biomarkers as an
example. Bladder cancer is selected because of its city? Thompson et al. 8 reported