Summary of main results
Our results found that, first, ROMA could help distinguish EOC from benign pelvic mass with a high diagnostic accuracy (AUC: 0.93). The ROMA has high sensitivity to predict advanced stage EOC than early stage EOC and in postmenopausal women than in premenopausal women. Second, although HE4 has higher specificity than CA125 for EOC monitoring, CA125 has better diagnosis accuracy (higher AUC) than HE4 for EOC or OC prediction. This is based on the results of 4 studies that compare HE4 and CA125 within the same population. Third, based on the results of comparison of HE4, CA125 and ROMA in the same population, the overall performance (AUC) of the three tests for EOC prediction are similar. ROMA is less specific but more sensitive than HE4, while both ROMA and HE4 are more specific than CA125 for EOC monitoring.
All studies included were subjected to close scrutiny with the QUADAS-2 tool, resulting in high quality across the items. Heterogeneity often existed in diagnostic meta-analysis [38
], and mainly resulted from characteristics of the study population, variations in the study design, different statistical methods, and different covariates [39
]. Within-study quality were highly concerned in this meta-analysis. Both high level of heterogeneity in sensitivity and specificity were found for ROMA test. The existence of threshold effect might partially explain the heterogeneity. Analysis of subgroups (EOC-methods high concern and EOC-methods low concern) found the EOC-methods High concern group had higher specificity than both EOC-methods Low concern group and EOC group.
In the current paper, only three studies evaluated the diagnostic value of ROMA at early stage of EOC. The early stage ovarian cancer usually presented non-specific clinical manifestation, and the FIGO staging by surgery often resulted in low prevalence of early stage EOC. So future clinical investigations will be promising and expectant to be prospective studies recruiting enough patients with early stage EOC.
We analyzed the predictive value of ROMA for patients with EOC, EOC(LMP/BL) and ovarian cancer. No differences were found in all summary estimates (except AUC between EOC and OC groups) of EOC, EOC (LMP/BL) and OC groups. Although EOC accounted for 90% of ovarian cancer, we didn’t think ROMA could be expanded to predict ovarian cancer, for both HE4 and CA125 were biomarkers of epithelial ovarian cancer[2
Cut-off values were variable for HE4 (70-150pM) and ROMA (preM: 7.4-13.1%; postM: 10.9-27.7%), but consistent for CA125 (35U/mL) across studies. Among the studies included, only one study[15
] used specific cut-off values for premenopausal (70pM) and postmenopausal women (140pM). Studies found that HE4 levels in healthy subjects were associated with age [40
]. So it would be essential to define a specific normal range and cut-off value for premenopausal and postmenopausal women respectively. For other two predictors ROMA and CA125, it would also be indispensable for each center to define their normal ranges and cut-off values.
Strengths and weaknesses
Except employing a comprehensive search strategy, strict inclusion criteria and sound analysis protocol, strengths of this paper also contain that only studies investigating both the two tests (HE4 and CA125) or all three tests (HE4, CA125 and ROMA) in a same population have been included in tests comparisons. The latter makes sure that the comparison takes place between studies under the same or similar population background, thus reduces the heterogeneity between studies [42
The main limitations are: (1) unable to gain the unpublished paper. (2) Study number might be small. We believe that reliability of the meta-analysis are majorly dependent on the quality of studies included. (3) The diagnostic value of ROMA, HE4 and CA125 in early stage EOC have not been convincingly analyzed.
ROMA can help distinguish EOC from benign pelvic mass. ROMA is less specific but more sensitive than HE4. Both ROMA and HE4 are more specific than CA125 for EOC prediction. CA125 has better diagnosis accuracy than HE4 for EOC and OC prediction. ROMA is promising predictor to replace CA125, but its utilization requires further exploration.
ROMA, Risk for ovarian malignancy algorithm; HE4, Human epididymis protein 4; EOC, Epithelial ovarian cancer; OC, Ovarian cancer; CA125, Cancer antigen 125; QUADAS-2, Quality assessment of diagnostic accuracy studies-2; DOR, Diagnostic odds ratio; LR±, Positive and negative likelihood ratio; AUC, Area under receiver operating characteristic-curve; CI, Confidence interval; FDA, Food and drug administration; EIA, Enzyme immunoassay; MOOSE, Meta-analysis of observational studies in epidemiology; FIGO, International federation of gynecology and obsterics; TPR, True positive rate; FPR, False positive rate; LMP, Low malignant potential tumors; BL, Borderline tumors; HSROC, Hierarchical summary receiver operating characteristic curves; CMIA, Chemiluminescent microparticle immunoassay; RIA, Radioimmunoassay; CLEIA, Chemilumenscence enzyme immunoassay; ECLIA, Electrochemilumenscence immunoassay.
Lili Yu declared a grant (NO. 81070505) from National Natural Science Foundation of China. For other authors none were declared.
FKL conceived the study, searched databases, extracted the data, performed the statistical analysis and drafted the manuscript. RXT selected the trials, extracted the data and helped draft the manuscript. KC and WPL participated in the selection of trials and the statistical analysis. FW searched databases, evaluated the studies included and revised the manuscript critically. SLD evaluated the studies included, participated in the coordination and revised the manuscript critically. LLY participated in the design, selected the trials and revised the manuscript critically. MC conceived of the study together with FKL, participated in the design and helped draft the manuscript. All authors read and approved the final manuscript.