Exploring the value of pleural fluid biomarkers for complementary pleural effusion disease examination
Graphical Abstract
Introduction
Lung cancer, the most frequent cause of cancer death, is also a major cause of the pleural effusion. Approximately 10% of lung cancer patients have pleural effusion at the time of initial diagnosis, while 30–40% develop it later in the course of their disease (Khan et al., 2013). One of the main issues in the differential diagnosis of pleural effusion is distinguishing exudates from transudates. Determining the nature of pleural effusion (exudate or transudate) allows reducing the list of potential pleural causes and indicates the direction for further diagnosis. Another important clinical issue is the etiology of effusion – malignant or benign – being crucial for pleural effusion management and prognosis. In clinical practice, the preoperative diagnosis etiology of pleural effusion still depends primarily on magnetic resonance imaging (MRI), computed tomography (CT), bronchoscopy, sputum analysis (Pongnikorn et al., 2018; Saraya et al., 2019). A biopsy followed by the histopathological examinations with high specificity is usually performed to confirm the diagnosis. In contrast, the conventional test biomarkers are less invasive and faster than histopathological examination, which has been widely used in supporting clinical tests (Porcel et al., 2004; Chen et al., 2006; Nicolini et al., 2008). Pleural fluid tests are a useful guideline when accessing the etiology of pleural effusions. The differences in pleural fluid biochemical profiles may in part mirror the relative contributions of diverse etiologies. The routine pleural fluid evaluation usually includes the character of the fluid (color, odor), specific gravity, pH level, lactate dehydrogenase (LDH), adenosine deaminase levels (ADA), glucose (GLU), total protein (TP) and cell count for differential and cytological examination.
To help differentiate the etiologies of pleural effusion, many studies have examined tumor markers, such as cytokeratin 19 fragments (CYFRA21–1), carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), as a possible alternative to invasive procedures (Porcel et al., 2004, Volarić et al., Feb. 2018, Duffy et al., 2007). Tumor markers have been extensively studied, but none are specific for detecting malignant pleural effusion (MPE) (Volarić et al., Feb. 2018, Lai et al., Sep. 1999). The value of individual tumor markers depends on the dominating mechanism involved in the development of the pleural effusion. The level of serum CEA was found to be significantly increased in tumors such as colorectal cancer (Duffy et al., 2007, Mroczko et al., 2007), breast cancer (Nicolini et al., 2008, Sölétormos et al., 2004) and endometrial cancer (Yurkovetsky et al., 2007). Also, serum CYFRA 21–1 concentrations were used primarily for the detection of colorectal cancer (Sawant et al., 2008), bladder cancer (ANDREADIS et al., 2005, Nisman et al., Jun. 2002), esophageal cancer (Shimada et al., 2005), and gynecological cancer (Pras et al., 2002, Yamamoto et al., 2005). On another hand, the median fluid concentrations for the investigated tumor markers were higher in malignant effusions than benign effusions (Korczynski et al., 2009). For example, the serum and pleural fluid levels of CYFRA21–1 are considered as a useful means in differentiating malignant from benign pleural effusion (Pras et al., 2002, Yamamoto et al., 2005). Besides, when CYFRA21–1 and CEA are combined, the diagnostic sensitivity for malignant pleural effusion would be superior, unlikely to CEA or CYFRA21–1 used alone (Saraya et al., 2019). These tumor markers exhibit great specificity, and the low sensitivity of each marker limits their diagnostic value. Some studies suggested that the analysis of tumor markers must be performed in combination with other pleural fluid tests for greater diagnostic accuracy (Chen et al., 2006, Trapé et al., 2017). The increasing number of tumor markers can improve detection efficiency, as well as reducing the specificity accordingly. Thus, monitoring of the type and number of tumor markers in pleural effusions can help to distinguish benign from malignant pleural effusions (Korczynski et al., 2009).
It is well known that there are many reports on the clinical application value of single or multiple combined biomarkers (Otoshi et al., 2017). However, whether it is based on single or multiple joint detections, it cannot simultaneously improve the specificity and sensitivity of the tested items at the same time. Recently, the combination of multiple biomarkers in this research group has improved the clinical diagnostic value of markers and basic theory for multidimensional analysis of biomarkers was provided (Zhang et al., 2018 Oct, Wu et al., 2019).
Deep learning is a multidisciplinary field combining computer science and mathematics and focused on implementing computer algorithms capable of maximizing predictive accuracy from statistic or dynamic data sources using analytical or probabilistic models. In the present study, the entropy weight method (EMW) which is a branch of information theory, that can capture the implied interactions among markers and determine the information weight of each marker, was used for deep learning. Combining clinical data using deep learning can enable the development of a novel model for distinguishing the etiology of pleural effusion. Furthermore, we investigate the contribution and direction of each variable within the model. The large number of biomarkers and their intertwining relations necessitates advanced deep learning models, rather than simple statistical and correlation analysis. The multidimensional combination of many biomarkers based on deep learning may assist effectively in the pleural effusion diagnosis. Moreover, the combination of biomarkers and deep learning led to enhancement in accuracy over single marker (Saleh et al., 2016).
This paper aims to investigate the discriminative properties of pleural fluid and serum biomarkers in distinguishing malignant and non-malignant pleural effusion. We also asked for the optimal combination of these markers to improve the diagnostic certainty in clinical use. The multidimensional combination of tumor markers, biochemical markers, and cytomorphological markers was explored by deep learning. It helps support the diagnosis etiology of pleural effusion, including malignant pleural effusion (MPE), parapneumonic effusion (PPE) and pleural effusion caused by congestive heart failure (CHF).
Section snippets
Patients and samples
A total of 276 pleural fluid samples were collected prospectively from 276 consecutive patients diagnosed with pleural effusion and admitted to the Clinical Laboratory at Tianjin Chest Hospital, China, from Jun 2018 until Jun 2019. Measurements were made at the time of admission to the Tianjin Chest Hospital. 193 patients had malignant pleural effusion (MPE) related lung cancer diagnosed by histologic and immunohistological analyses, 47 patients had parapneumonic effusion (PPE) resulting from a
Biomarkers for the determination of pleural effusion in three groups of diseases
According to the current guideline for medical examination of pleural effusion in China, the routine pleural fluid evaluation usually includes determination of physical character, biochemical markers, immune markers, pleural effusion cell counting, and classified counting according to cytomorphology after staining. The principle examinations and the approximate time consumption are listed (Table 1).
Comparison of biomarkers in three groups of pleural effusion
For each group, 11 indicators including ADA, TP, GLU, LDH, CEA, CYFRA21–1, NSE, WBC, MNC %, PNC
Discussion
According to the guideline of China Medical Examination of Pleural Effusion, the routine pleural fluid evaluation usually includes determination of the physical features of pleural fluid such as specific gravity, color, transparency; biochemical markers including pH level, TP, LDH, GLU, ADA, tumor markers (CEA, CYFRA21–1, NSE); WBC and the percentage of cells of various types (MNC%, PNC%, MTC%). Determining the diagnostic utility of pleural effusions markers has many advantages regarding both
Conclusions
Our study applied deep learning and entropy weight method to appraise the clinical value of pleural fluid biomarkers for the first time. As a result, a comprehensive examination of pleural fluid biomarkers is of high diagnosis ability and also suggests that we should attach special importance to cytomorphology tests in the pleural effusion routine examinations. In addition, the idea of combining pleural fluid markers and deep learning techniques could lead to an efficient future differential
Funding
This work was supported by the National Natural Science Foundation of China (Grant Nos. 61703304, 31600761).
CRediT authorship contribution statement
Pham Thi Huyen: Designed the study, Interpreted data, Wrote the manuscript. Lei Li: Made the clinical diagnosis. Meiyu Li, Zhexiang Wang: Collected samples and data. Sike Ma, Yan Zhao, Jing Yan: Performed data analyses. Meng Zhao, Xuguo Sun: Corrected the manuscript and contributed to the study design. All authors agreed with the results and conclusions.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
We are grateful to the patients, physicians, and pathologists at the Clinical Laboratory, Tianjin Chest Hospital, who contributed to patient material.
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