Detection of venous thromboembolism by proteomic serum biomarkers.
BACKGROUND
Available blood assays for venous thromboembolism (VTE) suffer from diminished specificity. Compared with single marker tests, such as D-dimer, a multi-marker strategy may improve diagnostic ability. We used direct mass spectrometry (MS) analysis of serum from patients with VTE to determine whether protein expression profiles would predict diagnosis.


RESULTS
We developed a direct MS and computational approach to the proteomic analysis of serum. Using this new method, we analyzed serum from inpatients undergoing radiographic evaluation for VTE. In a balanced cohort of 76 patients, a neural network-based prediction model was built using a training subset of the cohort to first identify proteomic patterns of VTE. The proteomic patterns were then validated in a separate group of patients within the cohort. The model yielded a sensitivity of 68% and specificity of 89%, which exceeded the specificity of D-dimer assay tested by latex agglutination, ELISA, and immunoturbimetric methods (sensitivity/specificity of 63.2%/60.5%, 97.4%/21.1%, 97.4%/15.8%, respectively). We validated differences in protein expression between patients with and without VTE using more traditional gel-based analysis of the same serum samples.


CONCLUSIONS
Protein expression analysis of serum using direct MS demonstrates potential diagnostic utility for VTE. This pilot study is the first such direct MS study to be applied to a cardiovascular disease. Differences in protein expression were identified and subsequently validated in a separate group of patients. The findings in this initial cohort can be evaluated in other independent cohorts, including patients with inflammatory conditions and chronic (but not acute) VTE, for the diagnosis of VTE.
Ganesh
Santhi K
SK
National Heart, Lung and Blood Institute, Bethesda, Maryland, United States of America; National Human Genome Research Institute, Bethesda, Maryland, United States of America.
Sharma
Yugal
Y
Dayhoff
Judith
J
Fales
Henry M
HM
Van Eyk
Jennifer
J
Kickler
Thomas S
TS
Billings
Eric M
EM
Nabel
Elizabeth G
EG
D000465:Algorithms; D014408:Biomarkers, Tumor / Q000097:blood*; D015331:Cohort Studies; D048909:Diabetes Complications / Q000097:blood; D015180:Electrophoresis, Gel, Two-Dimensional; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D006331:Heart Diseases / Q000097:blood / Q000150:complications; D006801:Humans; D007674:Kidney Diseases / Q000097:blood / Q000150:complications; D008171:Lung Diseases / Q000097:blood / Q000150:complications; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000150:complications; D016571:Neural Networks, Computer; D010865:Pilot Projects; D011379:Prognosis; D040901:Proteomics; D012680:Sensitivity and Specificity; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D054556:Venous Thromboembolism / Q000097:blood* / Q000175:diagnosis*
D014408:Biomarkers, Tumor; D005338:Fibrin Fibrinogen Degradation Products; C036309:fibrin fragment D