An Improved Prediction Model for Ovarian Cancer Using Urinary Biomarkers and a Novel Validation Strategy
Abstract
:1. Introduction
2. Results
2.1. Urinary Protein Biomarkers in Patients with Ovarian Cancer
2.2. Urinary Multimarker Panel Analysis in Patients with Ovarian Cancer
2.3. Clinical Characteristics of Difficult Samples to Predict
3. Discussion
4. Materials and Methods
4.1. Patient Populations and Urine Sample Collections
4.2. Multiplexed Urinary Biomarker Analysis
4.3. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
OC | ovarian cancer |
EOC | epithelial ovarian cancer |
SN | sensitivity |
SP | specificity |
RMI | Risk of Malignancy Index |
ROMA | Risk of Malignancy Algorithm |
FIGO | the International Federation of Gynecology and Obstetrics |
HE4 | human epididymis protein 4 |
VCAM | vascular cell adhesion molecule |
TTR | transthyretin |
CEA | carcinoembryonic antigen |
NCAM | neural cell adhesion molecule |
CA-125 | cancer antigen 125 |
CRP | C-reactive protein |
PDGF | platelet-derived growth factor |
MPO | myeloperoxidase |
IL | interleukin |
MIF | macrophage migration inhibitory factor |
ApoAI | apolipoprotein A1 |
ApoCIII | apolipoprotein C3 |
PAI-1 | plasminogen activator inhibitor-1 |
OPN | osteopontin |
LASSO | Least Absolute Shrinkage and Selection Operator |
PPV | positive predictive value |
NPV | negative predictive value |
AUC | area under the receiver operating characteristic curve |
CIs | confidence intervals |
IVDMIA | in vitro diagnostic multivariate index assay |
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Number of Totals | Premenopausal | Postmenopausal | |
---|---|---|---|
Total | 295 | 175 | 119 |
Age (years), median and range | 48 (20–82) | ||
Benign tumor | 125 (42.4%) | 99 | 25 |
Endometriosis | 44 | 41 | 3 |
Teratoma | 30 * | 27 | 2 |
Mucinous cystadenoma | 16 | 13 | 3 |
Serous cystadenoma | 9 | 5 | 4 |
Inflammation 1 | 5 | 1 | 4 |
Others 2 | 21 | 12 | 9 |
Borderline tumor | 12 (4.1%) | 10 | 2 |
Malignant tumor | 158 (53.5%) | 66 | 92 |
Serous adenocarcinoma | 111 | 40 | 71 |
Mucinous adenocarcinoma | 12 | 6 | 6 |
Endometrioid adenocarcinoma | 15 | 11 | 4 |
Clear cell carcinoma | 12 | 4 | 8 |
Other EOC 3 | 3 | 1 | 2 |
Granulosa cell tumor | 2 | 2 | - |
Dysgerminoma | 1 | 1 | - |
Other non-EOC 4 | 2 | 1 | 1 |
FIGO stage of malignancy | |||
I | 36 | 23 | 13 |
II | 12 | 5 | 7 |
III | 91 | 32 | 59 |
IV | 19 | 6 | 13 |
Markers | All Samples | Stage I and II | Stage III and IV | |||
---|---|---|---|---|---|---|
AUC | (95% CIs) | AUC | (95% CIs) | AUC | (95% CIs) | |
HE4 | 0.822 | (0.772–0.869) | 0.759 | (0.659–0.852) | 0.847 | (0.791–0.898) |
VCAM | 0.776 | (0.717–0.829) | 0.744 | (0.650–0.830) | 0.788 | (0.725–0.847) |
Leptin | 0.771 | (0.701–0.837) | 0.779 | (0.657–0.889) | 0.772 | (0.689–0.848) |
TTR | 0.767 | (0.706–0.824) | 0.789 | (0.714–0.856) | 0.757 | (0.693–0.819) |
Prolactin | 0.713 | (0.624–0.793) | 0.732 | (0.573–0.870) | 0.701 | (0.600–0.794) |
CRP | 0.710 | (0.644–0.772) | 0.644 | (0.541–0.743) | 0.734 | (0.662–0.800) |
PDGF-AA | 0.697 | (0.632–0.758) | 0.734 | (0.644–0.820) | 0.677 | (0.607–0.747) |
NCAM | 0.678 | (0.613–0.741) | 0.672 | (0.576–0.761) | 0.678 | (0.609–0.742) |
Mesomark | 0.670 | (0.578–0.756) | 0.648 | (0.520–0.769) | 0.680 | (0.583–0.769) |
MPO | 0.668 | (0.598–0.737) | 0.640 | (0.554–0.723) | 0.684 | (0.610–0.756) |
Cyfra21-1 | 0.660 | (0.591–0.726) | 0.728 | (0.630–0.821) | 0.628 | (0.549–0.701) |
CEA | 0.627 | (0.558–0.692) | 0.684 | (0.583–0.778) | 0.600 | (0.524–0.676) |
Creatinine | 0.622 | (0.554–0.687) | 0.678 | (0.585–0.770) | 0.596 | (0.518–0.668) |
CA19-9 | 0.598 | (0.529–0.666) | 0.578 | (0.470–0.678) | 0.604 | (0.528–0.677) |
IL6 | 0.576 | (0.450–0.701) | 0.490 | (0.323–0.657) | 0.599 | (0.459–0.730) |
MIF | 0.572 | (0.500–0.642) | 0.640 | (0.531–0.743) | 0.537 | (0.456–0.618) |
ApoAI | 0.557 | (0.485–0.623) | 0.517 | (0.422–0.612) | 0.569 | (0.493–0.644) |
ApoCIII | 0.524 | (0.448–0.600) | 0.580 | (0.466–0.687) | 0.562 | (0.479–0.644) |
PAI-1 | 0.523 | (0.446–0.598) | 0.514 | (0.417–0.616) | 0.533 | (0.451–0.611) |
CA125 | 0.523 | (0.453–0.591) | 0.486 | (0.370–0.597) | 0.533 | (0.456–0.611) |
OPN | 0.521 | (0.45–0.591) | 0.540 | (0.443–0.635) | 0.514 | (0.435–0.594) |
IL8 | 0.488 | (0.416–0.563) | 0.541 | (0.449–0.633) | 0.531 | (0.453–0.607) |
CA15-3 | 0.486 | (0.417–0.552) | 0.540 | (0.439–0.638) | 0.536 | (0.460–0.613) |
Markers | All Samples | Stage I and II | Stage III and IV | |||
---|---|---|---|---|---|---|
AUC | (95% CIs) | AUC | (95% CIs) | AUC | (95% CIs) | |
HE4 | 0.822 | (0.772–0.869) | 0.759 | (0.659–0.852) | 0.847 | (0.791–0.898) |
CEA | 0.627 | (0.558–0.692) | 0.684 | (0.583–0.778) | 0.600 | (0.524–0.676) |
TTR | 0.767 | (0.706–0.824) | 0.789 | (0.714–0.856) | 0.757 | (0.693–0.819) |
Creatinine (Cr) | 0.622 | (0.554–0.687) | 0.678 | (0.585–0.770) | 0.596 | (0.518–0.668) |
HE4+Cr | 0.904 | (0.854–0.938) | 0.825 | (0.740–0.910) | 0.926 | (0.888–0.972) |
HE4+Cr+CEA | 0.923 | (0.878–0.954) | 0.883 | (0.772–0.934) | 0.943 | (0.907–0.982) |
HE4+Cr+CEA+TTR | 0.938 | (0.900–0.964) | 0.932 | (0.844–0.970) | 0.946 | (0.911–0.983) |
Algorithm or Assay | N | SN (%) | SP (%) | PPV | NPV | AUC | |
---|---|---|---|---|---|---|---|
Serum Multimarker Panels | |||||||
Moore, 2010 [27] | RMI | 457 | 84.6 | 75.0 | - | - | 0.870 |
ROMA | 457 | 94.3 | 75.0 | - | - | 0.953 | |
Karlsen, 2012 [28] | RMI | 1218 | 96.0 | 75.0 | - | - | 0.958 |
ROMA | 1218 | 94.8 | 75.0 | - | - | 0.954 | |
Bristow, 2013 [30] | OVA1 | 494 | 92.4 | 53.5 | 31.3 | 96.8 | - |
Grenache, 2015 [29] | ROMA | 146 | 83.9 | 83.5 | 57.8 | 95.1 | - |
OVA1 | 146 | 96.8 | 54.8 | 36.6 | 98.4 | - | |
Urinary Biomarker | |||||||
Hellstrom, 2010 [22] | HE4 | 135 1 | 88.6 | 94.4 | |||
Liao, 2015 [15] | HE4 | 279 2 | 52.2 | 95.0 | |||
Urinary Multimarker Panel in this Study | |||||||
HE4+Cr+CEA+TTR | 283 | 81.0 92.9 | 95.3 75.2 | 95.3 81.3 | 81.3 90.1 | 0.938 |
Inflammatory Mediators | IL-6 1, IL-8 1, MPO 1, MIF 1, OPN 1 |
Tumor-associated antigens | CA19-9 1, CA15-3 1, CA-125 1, HE4 1, CEA 1 |
Adhesion molecules | VCAM1, NCAM 1 |
Adipokines | Leptin 1 |
Apolipoproteins | ApoAI 1, ApoCIII 1 |
Apoptotic proteins | Cyfra21-1 1 |
Growth/angiogenic factors | PDGF-AA 1 |
Carrier proteins | TTR 2 |
Proteases/inhibitors | PAI-1 1 |
Hormones | Prolactin 1 |
Others | CRP1, Mesomark 3, Creatinine 4 |
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Lee, S.-W.; Lee, H.-Y.; Bang, H.J.; Song, H.-J.; Kong, S.W.; Kim, Y.-M. An Improved Prediction Model for Ovarian Cancer Using Urinary Biomarkers and a Novel Validation Strategy. Int. J. Mol. Sci. 2019, 20, 4938. https://doi.org/10.3390/ijms20194938
Lee S-W, Lee H-Y, Bang HJ, Song H-J, Kong SW, Kim Y-M. An Improved Prediction Model for Ovarian Cancer Using Urinary Biomarkers and a Novel Validation Strategy. International Journal of Molecular Sciences. 2019; 20(19):4938. https://doi.org/10.3390/ijms20194938
Chicago/Turabian StyleLee, Shin-Wha, Ha-Young Lee, Hyo Joo Bang, Hye-Jeong Song, Sek Won Kong, and Yong-Man Kim. 2019. "An Improved Prediction Model for Ovarian Cancer Using Urinary Biomarkers and a Novel Validation Strategy" International Journal of Molecular Sciences 20, no. 19: 4938. https://doi.org/10.3390/ijms20194938