Development of sensitive and specific biomarkers for diagnosing pancreatic carcinoma is a critical problem because most of these patients remain asymptomatic at the early stage, and are surgically inoperable when diagnosed. Also, the conventional methods, such as enhanced-CT/MRI, serum CA19-9, CA-125, CEA, MMP-9, K-ras mutation and many others are not always helpful in making an early diagnosis, especially at the potentially resectable stage [3
The present meta-analysis has shown that the pooled sensitivity was 0.89, specificity was 0.93, and AUC was 0.97, indicating a relatively high level of overall accuracy. The DOR is a single indicator of test accuracy [31
] that combines the data from sensitivity and specificity into a single number. The DOR of a test is the ratio of the odds of positive test results if the subject has the disease to the odds of positive test results if the subject does not have the disease. The value of a DOR ranges from 0 to infinity, with higher values indicating better discriminatory test performance (higher accuracy). A DOR of 1.0 indicates that a test does not discriminate between patients with the disorder and those without it. In the present meta-analysis, we found that the pooled DOR was 115.13, also indicating a high level of overall accuracy.
The SROC curve and the DOR are not easy to interpret and use in clinical practice, while the likelihood ratio (PLR and NLR) is more clinically meaningful for our measures of diagnostic accuracy. A PLR value of 11.62 suggests that patients with PaC have about 11-fold higher chance of being miRNA assay-positive compared to patients without PaC, and this was high enough for the clinical purpose. The NLR was 0.14 in the present meta-analysis; it means that the probability of the patient having PaC is 14% if the miRNA assay is negative, which is not low enough to rule out PaC.
More than 20 miRNAs (miR-16, 20a, 21, 24, 25, 99a, 100, 135b, 125b, 155, 181a, 185, 191, 196a, 210, 212, 221, 301, 367a, let-7i, etc.) involved in this meta-analysis were analyzed. These miRNA biomarkers may provide new insight into the early detection of PaC. However, there is no standing panel of effective miRNAs. Lee et al
. designed a study of more than 200 miRNA precursors, 20 of which expressed aberrantly in pancreatic adenocarcinoma [18
]. Munding et al
. identified 78 misregulated miRNAs and discovered that miR-135b performed best in discriminating pancreatic ductal adenocarcinoma (PDAC) from CP [23
]. miR-21 was the most frequent one to be studied and its strong expression was expected to be an important indicator for predicting the poor survival of PaC [18
]. miR-155 has been identified as a biomarker of early pancreatic neoplasm based on its overexpression in ~80% of precursor intraductal papillary mucinous neoplasms (IPMN) by Wang et al
]. Serum CA19-9 is the most common conventional diagnostic maker for PaC. Liu et al
. found that the sensitivity and the specificity of combination (plasma miR-16+miR-196a+CA19-9) are better than CA19-9 alone for PaC screening of early tumors and differential diagnosis from CP [22
]. Of the nine studies included, only one study mentioned the threshold from a training set of 20 specimens, suggesting that computing Ct(miR-135b)-Ct(miR-24) has the most discrimination potential. Therefore, more studies should be designed to define distinct miRNA expression profiling. And multi-center, prospective clinical studies on a large scale should be carried out to identify novel miRNA or the most effective combination of miRNA in the diagnosis of PaC.
Mitchell et al
. showed that plasma-based miRNAs are remarkably stable for they are protected from endogenous RNase activity [32
]. This meta-analysis also respectively analyzed the sensitivity and specificity of tissue-based and blood-based miRNA assays. Our results indicated that the blood-based level of miRNA can distinguish PaC with more significant sensitivity and specificity than tissue-based miRNA. Therefore, the development of blood-based (plasma or serum) biomarker assays may be the most desirable non-invasive method of choice for screening and diagnosing PaC in the future.
Our meta-analysis has several limitations. Firstly, although we used a comprehensive search strategy, and the screening, study selection, data extraction and quality assessment were done independently and reproducibly by two reviewers, there were only seven publications included, and the limited patient numbers may have influenced the outcomes, so it is still hard to make a definitive conclusion about the accuracy of diagnosis of PaC; hence, further studies on a large scale may be needed to confirm the diagnostic value of miRNA assay in PaC. Secondly, due to the limited studies included, we did not use QUADAS scores to perform a meta-regression analysis to assess the effect of study quality on relative DOR of miRNA assay in the diagnosis of PaC. And for the same reason, we could not explore whether the study design, such as blinded, cross-sectional, consecutive/random and prospective design, affects the diagnostic accuracy, either.
In conclusion, the present meta-analysis suggests a potential role for miRNA assays in screening and confirming a diagnosis of PaC. Further studies are required to confirm the predictive value. Since none of the biomarkers including miRNAs is special for PaC, the results of miRNA assays should be interpreted in parallel with clinical findings and the results of conventional tests.