Biology Reference
In-Depth Information
Table 19.1B
Candidate Acute GVHD Biomarkers with Diagnostic and Prognostic Significance Identified with Proteomics
Discovery—cont'd
No. of
Patients in
Study
Biofluid
Source
Target
Organ
Protein
Reference
Methods
Diagnosis
Prognosis
Predictive
SLPI
[17]
Saliva
SELDI-TOF
2D-DIGE
ELISA
41
Systemic
Yes
ND
ND
TNFR1
[12]
Plasma
Antibody
microarrays
followed by
ELISA
42+ 282
*
+
142
*
Systemic
Yes
Yes
ND
ND, not done; TRC, transplant-related complications.
*Validation sets.
comprehensive assessment of plasma protein levels such as those described
above might provide an integrated view of a systemic disease such as GVHD.
To identify systemic GVHD biomarkers, our approach was to screen patient
plasma samples by competitive hybridization to arrays of antibodies spe-
cific for 120 diverse proteins, including acute-phase reactants, cytokines,
angiogenic factors, tumor markers, leukocyte adhesion molecules, metal-
loproteinases, and their respective inhibitors. We used array technology
during the discovery phase followed by ELISA to quantify the concentra-
tions of individual proteins. To validate this aGVHD biomarker panel, we
randomly divided the samples into a training set of 282 patients and a
validation set of 142 patients, which is currently one of the most reliable
approaches for validation. In this statistical analysis, the best classification
and prediction model is evaluated using the training set and subsequently
applied and verified in the validation set. Thus, the validation set represents
a more objective measure of biomarker performance. This approach iden-
tified and validated a four-protein biomarker panel (IL-2Rα, TNFR1, IL-8,
and HGF) with high specificity for GVHD diagnosis. All four of the biomark-
ers identified had been associated with GVHD in previous small studies
[46,47,49,50,52,53,59]
. Because of the large size of our study, we provided
the first demonstration that these biomarkers are associated with GVHD
clinical outcomes and prognosis
[12]
.
466
TARGET-SPECIFIC BIOMARKERS OF aGVHD
Clinical symptoms of the skin (e.g., maculopapular rash) and GI tract (e.g.,
nausea, diarrhea) caused by GVHD can be difficult to distinguish from other
causes (e.g., infectious, drug-induced). Thus, biomarkers that are GVHD
and target specific may improve the diagnosis of complications post-HSCT.
Because biomarkers present at the time of GVHD diagnosis might differ
between target-specific GVHD, we sought to identify biomarkers that were
specific for GVHD target organs to improve the diagnostic and prognostic
values of the systemic panel by comparing patients with skin-specific or
GI-specific GVHD to patients without GVHD. While the antibody biomarker
screen can be considered internally unbiased because each antibody is
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