Theme trends in research related to retinal vein occlusion: a quantitative and co-word analysis

Abstract

BACKGROUND

Retinal vein occlusion (RVO) ranks the second most common cause of retinal vascular disease [1]. Central (CRVO), hemiretinal (HRVO) and branch (BRVO) vein occlusion are the three major categories of RVO based on the occlusion site. Patient symptoms may generally include, depending on the classification of RVO, blurry or missing vision, floating dots or lines, and defective visual field. The main complications of CRVO include the macular edema formation, neovascularization, neovascular glaucoma, and vitreous hemorrhage, while complications of BRVO depend more on the vessel occluded [2]. Academic journals have published a vast amount of papers in RVO related research over recent decades. In order to reduce the effort and time required for a traditional systematic literature review, we applied bibliometric methods to explore the research status in an RVO study.

Bibliometry is a computational analytical method, which is based on mathematical and statistical analysis of an article’s attributes, and it can be used to describe, assess and predict the current status and future development of science and technology [3]. Co-word and co-citation analyses are the common means employed in bibliometry analysis to demonstrate research trends. It is assumed that a collection of academic words from an article of interest can be used to outline this article. Based on this presumption, co-word analysis can be employed to assess the relationship of two academic words in an research literature. This study is focusing the assessment of RVO research trends with co-word analysis.

METHODS

Data Collection

Medical subject headings (MeSH) is a universal terminology used in academic publications to index and categorize biomedical information. In general, approximately ten to fifteen titles and subtitles are applied to index each published paper [4]. Co-word clustering analysis can be performed based on MeSH terms. In this study we select all journal articles in English from the PubMed database with the MeSH term “retinal vein occlusion”, and 3179 articles in total were identified and used in our analysis.

Data Extraction and Bibliographic Matrix Setup

Bibliographic Item Co-occurrence Matrix Builder (BICOMB), designed and built by Prof. Cui from China Medical University, was employed to examine the distribution features including publication time, nations, journals and researchers. In addition, BICOMB was also used to obtain the main MeSH terms/MeSH subheadings of these selected literatures [5]. The inventory, acquired from the PubMed database, was implemented for the generation of a term-source and co-occurrence matrix, and these matrices were further applied for subsequent bibliometric analysis.

Bi-clustering analysis of the high-frequency main MeSH terms/MeSH subheadings

Threshold value, T= (1+)/2, was used to evaluated the quantity of high-reoccurrence main MeSH terms/MeSH subheadings, and in this equation, “i” represents the quantity of key MeSH terms/MeSH subheadings with single appearance. RVO hot spots was explored with bi-clustering analysis which was based on the evaluation of high-reoccurrence MeSH terms and RVO-associated research articles. A binary matrix, with its rows built with high-reoccurrence key MeSH terms and its columns composed of source article, was developed. Then, the term-source article matrix was used to conduct co-occurrence double cluster analysis with gCLUTO software which can be retrieved from http://glaros.dtc.umn.edu/gkhome/cluto/gcluto. For hill diagram visualization, peaks are in accordance with the hotspots of the theme, which can be used to roughly estimate the clustering results. The different color appearing on the hill diagram represents different standard deviation (SD), the height of the hill is proportional to the similarity in intra-class and the hill volume is correlated with the quantity of MeSH terms. For dendrogram, high-reoccurrence key MeSH terms were displayed as the row labels and the PubMed Unique Identifiers (PMIDs) of the source publications were listed as the column names.

Strategic diagram analysis

The strategic diagram analysis is based on themes of centrality and density. Centrality is represented by the external cohesion index, indicating the them position in the framework, and density is illustrated by the internal cohesion index, reflecting the progression of the themes. With X-axis representing centrality and Y-axis illustrating density, four quadrants were developed. Based on the biclustering assessment, different clusters generated were distributed in different quadrants of this strategic diagram generated by Graph.

Social network analysis

SNA network was developed using Ucinet 6.0 (Analytic Technologies Co., Lexington, KY, USA) software according to the high-reoccurrence key MeSH terms/MeSH subheadings co-occurrence matrix. A two-dimensional map, for visualization, was generated with the key MeSH terms/MeSH subheadings using NetDraw 2.084 software. On this map, the key MeSH terms/MeSH subheadings were shown as the nodes and the frequency of their co-occurrence was displayed as the links. Furthermore, closeness, betweenness and degree centralities were employed to examine the location of the key MeSH terms/MeSH subheadings, in order to obtain in-depth understanding of RVO network organization.

RESULTS

Distribution characteristics of relevant literatures

With the searching criteria described above, 3179 publications in total were included in this study. As displayed in Fig.1A, research articles published yearly in the RVO field has gradually increased from 90 in 2004, to over 200 in 2015. Among all the first authors involved in this topic, Noma H ranked first by publishing 52 articles (Fig.1B). As for the amount of RVO research output, the United States ranked first with 1,544 publications, making up almost 50% of the research in this specific area (Fig.1C). Among the top 10 most productive journals displayed on Fig.1D, Retina, American Journal of Ophthalmology and Ophthalmology are listed as the top three, and these identified top journals are considered to be the principal journals in RVO field.

Research hot spots identification with MeSH term clusters

According to Table 1, 73 MeSH terms, representing 57.6% all MeSH terms, were identified as the high-reoccurrence MeSH terms. These 73 high-reoccurrence MeSH terms could be used to reveal the hot spots of studies in the field of RVO.

The visualization of the key MeSH terms/MeSH subheadings using the hill diagram and dendrogram, based on biclustering analysis, are presented on Fig. 2. According to the evaluation of the MeSH terms, RVO research hot spots were classified into five categories (Table 2). These categories mainly include the following content: (1) Research related to the epidemiology and metabolism of RVO (cluster 0); (2) Studies on the complications of RVO, and the etiology of macular edema; the therapeutic use of monoclonal/humanized antibodies, glucocorticoids, triamcinolone acetonide, dexamethasone and anti-inflammatory agents (cluster 1); (3) Surgical treatment of vitrectomy (cluster 2); (4) Genetics related research on RVO (cluster 3); and (5) Pathology of RVO and diagnostic methods including fundus fluorescein angiography (FFA) and optical coherence tomography (OCT) (cluster 4). The key research topics of RVO could be revealed by the above mentioned five clusters.

With the focus on investigating the structures of RVO knowledge systemically, co-word evaluation, biclustering examination, strategic diagram and bibliometric SNA were included in this study. Clusters were formed and identified with MeSh terms that are associated closely through the co-word and biclustering evaluation. Cluster 1 was identified to be associated with studies on the complications of RVO, the etiology of macular edema and the therapeutic use of monoclonal/humanized antibodies, corticosteroids and anti-inflammatory agents. Age and systemic disorders were identified as the top two risk factors for RVO. RVO prevalence increases significantly with age but does not differ by gender [6], probably due to atherosclerosis. Systemic diseases such as hypertension, diabetes mellitus, hyperlipidemia, thrombophilia, hypercoagulation and inflammatory diseases are strongly associated with RVO [7]. RVO patients may suffer a variety of complications, the most significant of which is macular edema. Other serious complications include vascularization of the retina and optic disc (which can result in vitreous hemorrhage), retinal detachment, neovascular glaucoma and even blindness [8]. Cystoid macular edema (CME), which is caused by capillary congestion, may result in the metamorphopsia and even loss of visual acuity. A multicenter, randomized clinical trial examined the efficacy and safety of 1-mg and 4-mg doses of intravitreal triamcinolone acetonide (IVTA) in comparison with standard grid photocoagulation for BRVO. Investigators reported similar improvement in OCT thickness over 1-year observation in all groups. In terms of complications, cataract progression rate was higher in the 4mg IVTA group, thus IVTA is less commonly used than anti-VEGF therapy [9]. VEGF is an inflammatory cytokine that promotes vascular permeability and is upregulated in eyes with vein occlusion [10]. Ranibizumab and bevacizumab are humanized monoclonal antibodies that are active against the VEGF-A molecule. Different clinical trials on anti-VEGF injections suggest that intraocular anti-VEGF injection can significantly improve vision acuity in eyes with BRVO [11]. These topics in Cluster 1, positioned in Quadrant I, are the centralized and matured hotspots in the RVO field.

Cluster 0 is associated with research on epidemiology and the metabolism of RVO. The prevalence of RVO has been reported to range between 0.4% and 4.6%. Of the two main types of RVO, BRVO is four to six times more prevalent than CRVO [12]. The balance between inflammatory cytokines and angiogenesis in eye fluid is disturbed in patients with RVO. Exposure of endothelial cells to proinflammatory cytokines can cause oxidative stress and apoptosis, aggravating leukocyte efflux and thrombosis. Significantly increased concentrations of IL-1α, -6, and -8; IP-10; and PDGF-AA were observed in RVO patients when compared to control patients [10]. Macular edema secondary to RVO is associated with increased levels of VEGF in the aqueous humor. Therefore, the management of macular edema secondary to RVO, especially in the presence of capillary con-perfusion areas, should aim at reducing ocular VEGF concentration [13]. Cluster 3 relates to genetic studies on RVO. Thrombophilic diseases like factor V Leiden mutation, hyperhomocysteinemia and anticardiolipin antibodies increase the risk of RVO [14]. Proteomic studies suggest that RVO is associated with the remodeling of the extracellular matrix and adhesion processes. However, many areas of proteome changes in RVO remain unstudied. Future studies may address long-lasting retinal changes following intervention with anti-VEGF agents, such as dexamethasone intravitreal implants [15]. These two clusters, assigned to Quadrant III, represents research hotspots which are marginal and immature, and future research on these topics is suggested.

Cluster 2 relates to the surgical treatment of RVO. Macular grid laser photocoagulation is an effective treatment for macular edema in patients with BRVO. Other treatment options for reducing edema are intravitreal steroids, anti-VEGF drugs and vitrectomy. It has also been reported that vitrectomy is effective for reducing macular edema and improving visual acuity in patients with BRVO. Vitrectomy probably reduces macular edema by allowing oxygenated fluid to circulate in the vitreous cavity, improving perifoveal microcirculation, and increasing the clearance of VEGF in the vitreous cavity. A five-year follow-up of vitrectomy for macular edema associated with BRVO revealed that vitrectomy may evade the risks associated with repeated injections; however, the incidences of postoperative RD were higher than that of intravitreal injections [16]. Cluster 4 is associated with the pathophysiology and RVO diagnosis. In RVO patients, signs of oxidative stress, such as enhanced plasma lipid peroxidation and decreased antioxidant activity of paraoxonase, have been reported [17]. M. Becatti, et al. compared ROS production and membrane lipid peroxidation in RVO patients and control subjects. The results indicated that erythrocyte oxidative stress is an essential factor in the pathogenesis of RVO disease [18]. Suzuki et al. reported that anti-VEGF therapy might improve retinal deep ischemia in the retinal deep layer of patients with RVO [19]. In clinical practice, treatment decisions commonly depend on OCT measurements. OCT provides high-resolution imaging of the fovea and is helpful in detecting the presence of macular edema, vitreoretinal interface changes, neurosensory retinal detachment and subretinal fluid. Optical coherence tomography angiography (OCTA) can evaluate the retinal hemodynamics in patients with RVO. FFA is able to detect peripheral capillary nonperfusion, macular ischemia, and subtle neovascularization. Eyes with more capillary nonperfusion have a greater risk of ocular neovascularization. FFA may also help to distinguish collateralization from neovascularization, since the former does not leak fluorescein, whereas the latter does [20]. These two clusters are assigned to Quadrant IV and include immature but centralized research topics.

According to the RNA analytical outcome, MeSH terms ranked the top three are “Macular edema/drug therapy”, “Antibody, monoclonal, humanized/therapeutic use” and “Retinal vein occlusion/drug therapy”, showing high degree centralities. These MeSH terms are with the most directly links with other components, pioneering the progress of the RVO research. With regard to the betweenness centrality analysis, “Retinal vein occlusion/complications”, “Retinal vein occlusion/diagnosis” and “Retinal vein occlusion/physiopathology” are identified to be located at the network center, representing the key components with the highest influence in the determination of other components’ co-occurrence. “Retinal vein/pathology” and “Retina/pathology” are among the top ten MeSH terms with betweenness centrality; however, these two components are located in the IV quadrant and are not included in the MeSH terms listed with the top ten high-reoccurrence. This demonstrates that although these two components are important in the network stability, but the research on this topic is not well developed.

CONCLUSIONS

In summary, the structure and maturity of an identified field can be evaluated and revealed with clustering analysis and strategic diagrams. SNA has the advantage of identifying the associations among the high-reoccurrence MeSH terms. The key foci on current research include drug therapy and pathogenesis alterations, and genetics-based studies are the novel developing areas. The purpose of this bibliometric study is to shed some light on research topic selection for researchers in the RVO field. However, potential methodological limitations should also be evaluated by researchers. First, the publications extracted from PubMed may not be comprehensive enough to cover all of the topics in RVO literature. Secondly, research article and journal qualities are not consistent, with articles from top tier journals showing significant impact in comparison with those of little influence from inferior journals. Thus, the contribution should have not be considered the same in the knowledge structure during analysis. Finally but not lastly, high-reoccurrence MeSH terms were used for the co-word analysis and novel research topics may be excluded from the analysis due to low-reoccurrence, which may introduce bias during the analysis. Due to the above potential limitations, future analyses should take the newly emerging topics and multiple databases into consideration.

DECLARATIONS

Acknowledgements

The authors would like to thank the editor and all reviewers for their valuable comments to improve the quality of this paper.

Funding

This work was supported by Norman Bethune-Lumitin Young and middle-aged ophthalmic research fund (No. BJ-LM2015009L). The Funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Availability of data and materials

The datasets included in this study are available in the PubMed database.

Author contributions

FL conceived the rearch, finished the manuscript and reviewed the final version. XC and MZ extracted data and prepared figures/ tables. All authors have read and approved the manuscript.

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable

Competing interests

No competing interests.

Abbreviations

RVO: retinal vein occlusion; CRVO: central retinal vein occlusion; HRVO: hemiretinal retinal vein occlusion; BRVO: branch retinal vein occlusion; BICOMB: Bibliographic item co-occurrence matrix builder; SNA: social network analysis; MeSH: Medical subject headings; FFA: fundus fluorescein angiography; OCT: optical coherence tomography; OCTA: optical coherence tomography angiography; CME: cystoid macular edema; IVTA: intravitreal triamcinolone acetonide.

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