Endometriosis and its global research architecture: an in-depth density-equalizing mapping analysis

Background: Endometriosis is one of the most common gynecological diseases. It is still a chameleon in many aspects and urges intense research activities in the fields of diagnosis, therapy and prevention. Despite the need to foster research in this area, no in-depth analysis of the global architecture of endometriosis research exists yet.

We here used the NewQIS platform to conduct a density equalizing mapping study, using the Web of Science as database with endometriosis related entries between 1900 and 2009. Density equalizing maps of global endometriosis research encompassing country-specific publication activities, and semi-qualitative indices such as country specific citations, citation rates, h-Indices were created.

In total, 11,056 entries related to endometriosis were found. The USA was leading the field with 3705 publications followed by the United Kingdom (952) and Japan (846). Concerning overall citations and country-specific h-Indices, the USA again was the leading nation with 74,592 citations and a modified h-Index of 103, followed by the UK with 15,175 citations (h-Index 57). Regarding the citation rate, Sweden and Belgium were at top positions with rates of 22.46 and 22.26, respectively. Concerning collaborative studies, there was a steep increase in numbers present; analysis of the chronological evolution indicated a strong increase in international collaborations in the past 10 years.

This study is the first analysis that illustrates the global endometriosis research architecture. It shows that endometriosis research is constantly gaining importance but also underlines the need for further efforts and investments to foster research and ultimately improve endometriosis management on a global scale.

Endometriosis, Density equalizing, Mapping, Research architecture

Endometriosis is one of the most common benign gynecological diseases affecting 1 in 10 women of child- bearing age; its management constitutes a daily routine in the practice of obstetrician/gynecologists [1 –3]. In the United States (USA), it represents the third leading cause of gynecologic hospitalization, limits workforce participation and impacts both a woman ’s physical and mental well being [4]. Hence, endometriosis poses a tre- mendous burden on individual and community health: In the USA alone, the related total societal costs were pro- jected at $70 billion in 2009 [5]. Endometriosis is an estrogen-dependent condition char- acterized by endometrial glands and stroma located out- side the uterine cavity [6 –9]. Implants are found in the peritoneum, the ovaries and the rectovaginal septum constituting three different disease entities [10]. Endo- metriosis is a commonly underdiagnosed condition: Its epidemiologic assessment is hampered by a high num- ber of obscure cases in the general population and the lack of non-invasive diagnostic tools [11, 12]. However, endometriosis is estimated to have a prevalence of up to 5 % in fertile and 25 –40 % in infertile women [8]. * Correspondence: [email protected] 1Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, 2020 Zonal Ave, IRD 509, Los Angeles 90089-9300, CA, USA 2Institute of Occupational Medicine, Social Medicine and Environmental Medicine, Goethe-University, Theodor-Stern Kai 7, 60590 Frankfurt, Germany © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Brüggmann et al. BMC Women's Health (2016) 16:64 DOI 10.1186/s12905-016-0336-0 Additionally to debilitating symptoms such as dysmen- orrhea, chronic pelvic pain and infertility, 8 –30 % of patients will develop endometriosis-associated ovarian cancer during their lifetime [13 –1 5 ] .C u r r e n t l y ,t h e r ei s no cure for endometriosis but several treatment proto- cols exist for the management of associated sequelae [8, 16, 17]. Although substantial progress has been achieved investigating the pathogen esis and pathophysiology of the disease, endometriosis still belongs to the most enigmatic and complex conditions in the field of ob- stetrics and gynecology (OB/GYN). Further multidis- ciplinary, translational and clinical research is needed [4, 11, 18] to define disease origins, to develop non- invasive diagnostic tools and in-vitro models aiming to evaluate the process of malignant transition as well as novel treatment approaches [6, 12, 19, 20]. In this respect, it is commonly accepted that further random- ized clinical trials, which focus on proposed etio- pathogenic mechanisms and therapeutic innovation, are necessary to identify more conclusive, evidence- based answers [8]. Besides posing a scientific challenge, endometriosis constitutes a major burden on female health worldwide. Hence, we deduce that research and public health ef- forts have to be strengthened to ensure future suc- cesses. To plan these research endeavors accordingly so they meet identified shortcomings and to supply deci- sion makers with information concerning funding strat- egies, it is the objective of the study to assess the present scientific performance in the field. The ‘New Quality and Quantity Indices in Science ’ (NewQIS) pro- ject [21, 22] combines scientometric tools and advanced density equalizing mapping procedures [23] to depict the global research architecture and to evaluate country-specific productivity in the framework of the scientific landscape. We also aim to guide individual scholarship and the publication of own research by pre- senting the 10 most cited articles and the most prolifer- ative journals in the field of endometriosis research.

NewQIS protocol We employed the previou sly established NewQIS platform to conduct this study [21, 22]. The method encompasses the use of advanced visualization algo- rithms such as Gastner and Newman ’s density equal- izing calculations and scientometric tools in order to evaluate and visualize endo metriosis-associated re- search activity [21, 22]. Data source As described previously [24, 25], the database Web of Science (WoS, Thomson Scientific) was used for data collection. We based this study on this particular re- source because WoS provides the unique opportunity to analyze the global public ation activity and to per- form an in-depth citation analysis, which includes the calculation of combined semi-qualitative country- and endometriosis-specific indices such as the modified h- indices or average citation rates. Search strategy In the presented approach, we identified endometriosis- specific publications by the use of the specific search term ‘(endometrios*)’. The operator * was applied to identify both singular and plural cases in title, abstract and key words of all eligible publications listed in the WoS. Timeframe The search was performed in 2010; the analyzed time- frame covered the years between 1900 (01-01) and 2009 (31-12). As discussed in previous studies, results from 2010 onwards were not considered due to incomplete data acquisition (i.e. citation rate) in order not to ham- per the global citation analyses. Data analysis and categorization All endometriosis-related publications issued in the timeframe of 110 years were analyzed using our stan- dardized protocol and categorized with respect to publi- cation date, country of origin, source title, and authors [26]. Also, the numbers of citations were retrieved for each publication and the average citation per item (CR, citation rate) were calculated as previously described. After transfer the raw data to excel charts, the findings were illustrated in diagrams and visualized by density- equalizing mapping projections (DEMP) [26]. The current DEMP analysis was based on the algorithm of Gastner and Newman [23], so the territories of the different coun- tries publishing endometriosis research were resized in proportion to our selected variables. In the present con- text, we used these visualization algorithms to draw a sketch of worldwide endometriosis-related research activ- ities illustrating the global distribution of country-specific numbers of published items and related citation rates. Analysis of research cooperations To investigate endometriosis-related research collabora- tions between the different countries, the affiliations of the endometriosis-related publications were screened as earlier described for other diseases [24, 26]. If at least two authors, attributed to different countries, contrib- uted to an endometriosis article, this relationship was defined as a collaborative publication. Brüggmann et al. BMC Women's Health (2016) 16:64 Page 2 of 12 Journal analysis We evaluated journals publishing endometriosis research by analyzing quantitative and qualitative aspects, e.g. number of published endometriosis-specific articles as well as citations these items received (CR).

Global endometriosis research activity In total, 11,056 endometriosis-related publications were identified. These items were published in 20 different lan- guages: 93.0 % were written in English, 3.4 % in German, 2.3 % in French, and 0.5 % in Spanish, respectively. Out of 11,056 publications, 10,881 were attributed to one or more originating countries and issued by authors from 88 nations. The USA was most productive with 3705 publications (p). It was followed by the United Kingdom (UK, p: 952), Japan (p: 846), Italy (p: 720), Germany (p: 715), France (p: 497), Belgium (p: 378), Canada (p: 375), Australia (p: 270) and Spain (p: 213). In the DEMP-analysis (Fig. 1a), major parts of Asia in- cluding Russia and China (with the exception of Japan), Africa and South America (except Brazil), appear mini- mized. The DEMP visualizes that North America clearly constitutes the scientific center of endometriosis research, followed by Western Europe. In the analysis of the chronological evolution of endo- metriosis research (Fig. 1b), a significant increase in an- nual publication numbers was visible from 1980 onwards. The steep increase after 1990 can be explained by the fact that the WoS started to include abstracts of the publica- tions in the database, which increased the likelihood to identify endometriosis-related items by topic search. Cor- respondingly, a larger number of publications and related citations could be identified in our search. The years with the highest publication activities included 2007 (746 an- nual publications), 2009 (739 annual publications) and 2008 (726 annual publications). The highest growth in publication output was present between 2002 and 2003 with an increase from 428 to 618 %. In the last 10 years of our analysis spanning 110 years of endometriosis research, 6221 publications were published (equals 56 % of all). Citation analysis In the country-specific citation analysis (Fig. 2a), again, the USA was found to be the leading nation with a total of 74,592 citations, followed by the UK with 15,175 cita- tions, Japan with 11,704 citations and Italy with 10,147 citations. DEMP results of total citations resembled the aforementioned DEMP analysis of total publications numbers with some minor exceptions, i.e. Belgium was ranked 5 th with 8489 citations (Fig. 2a). In Additional file 1, we compiled the 10 most cited articles in the field. The calculation of the country-specific citation rate (citations per endometriosis publication of a country, with a threshold of 30 publications per country) was used as a semi-qualitative measure (Fig. 2b). It pointed to a high average citation of Belgian endometriosis pub- lications with a citation rate (CR) of 22.46 citations per single endometriosis publication. Sweden was located in the second position with a rate of 22.26 followed by Finland (CR 20.77), the USA (CR 20.13), Norway (CR 19.42), the Netherlands (CR 17.19), Canada (CR 16.69) and the UK (CR 15.94). The country- and endometriosis-specific h-Index cal- culation (Fig. 2c) demonstrated a leading position of the USA with 103 endometriosis-related publications cited at least 103 times. The USA is followed by the UK with a country-specific h-Index (HI) of 57, Belgium (HI 49), Italy and Japan (HI both 47), France (HI 42) and Canada (HI 41). Again, countries from Asia (with the exception of Japan), Africa, Eastern Europe, or Latin America were characterized by very low citation rates. Cooperation articles In the period between 1900 an d 2009, 902 of all publica- tions were based on international collaborative efforts. This equaled a rather low percentage of 8.15 %. 771 of these items were issued by bilateral collaborations (85.5 %, Fig. 3a), followed by trilateral (101 publications) and collab- orations between four countries (20 publications). Analysis of the chronological evolution indicated a strong increase in international collaborations in the past 10 years (Fig. 3b). Overall, the USA dominated the category of collaborative efforts in the field of endometriosis research; 493 publica- tions could be attributed to international cooperations. It was followed by the UK (197 papers based on international collaborations out of 952 items in total), Germany (130 pa- pers based on international collaborations out of 715 items in total), Belgium (129 papers based on international col- laborations out of 378 items in total), and Italy (121 papers based on international collaborations out of 720 items in total). The USA established 75 bilateral collaborations with Canada, 61 with Germany and 61 with the UK. Other fruit- ful collaborations were identified between Belgium and the UK (39 items), Japan and the USA (38 items), Belgium and Kenya (34 items), Italy with the UK (34 items) and Italy with the USA (32 items, Fig. 4a). Among the ten countries having issued the most cooperation articles in the field, the percentage of publications based on international collab- orative efforts were the lowest in Japan (9 %) and the USA (13 %). Belgium and Sweden constituted notable excep- tions. These countries published more than a third of their total research output on endometriosis within the frame- work of international cooperations (Fig. 4b). Subject area analysis Most endometriosis publications were assigned to one (6151) or two (4592) subject areas (Fig. 5a). We Brüggmann et al. BMC Women's Health (2016) 16:64 Page 3 of 12 identified ‘Obstetrics and Gynecology ’ as the most fre- quently applied subject category with 6634 assignments followed by ‘Reproductive Biology ’ with 3410 assign- ments. Then, separated by a large gap, ‘Medicine, Gen- eral & Internal ’ was found (806 assignments), followed by ‘Surgery’ (588 assignments), ‘Pathology’ (532 assign- ments) and ‘Endocrinology & Metabolism ’ (512 assign- ments) (Fig. 5b). The most frequent combination of two assigned subject areas was ‘Obstetrics & Gynecology ’ with ‘Reproductive Biology ’ attributable to 3014 publications. When focusing on differences in subject areas between the 15 most productive countries in endometriosis re- search, no large differences were found. Journal analysis The 15 most prolific journals in endometriosis re- search were identified and illustrated in Fig. 6. “Fertility and Sterility” was leading the field (1837 articles), followed by “Human Reproduction” (721 articles) and the “American Journal of Obstetrics and Gynecology ” (501 articles). The Fig. 1 a Density-equalizing map of total endometriosis publications in each country. The area of each country was scaled in proportion to its total number of publications. Different colors encode numbers of endometriosis publications. This DEMP figure was generated by the authors as described in the methods section. b Chronological evolution of endometriosis-related publications. The red dotted line indicates the steep increase in publication activity visible after 1990 Brüggmann et al. BMC Women's Health (2016) 16:64 Page 4 of 12 highest citation rate was achieved by the “Journal of Clinical Endocrinology and Metabolism ” (104 articles, CR = 48.66).

As elegantly described by Kvaskoff et al., the etiology of endometriosis remains poorly understood despite an es- timated prevalence of 10 % in women [9]. The authors stress the fact that many unsolved questions still exist since endometriosis has been associated with an in- creased risk of several debilitating and chronic condi- tions, such as ovarian cancer, asthma, autoimmune, atopic and cardiovascular diseases [9]. Therefore, it is commonly accepted that a deeper understanding of these associations is needed as they may provide novel insights into the etiology or clinical implications of the Fig. 2 a Density-equalizing map of country total citations of endometriosis publications. The area of each country was scaled in proportion to its total number of citations. Colors encode numbers of citations. b Density-equalizing map of country citation rate of endometriosis publications. The area of each country was scaled in proportion to its citation rate. Colors encode numbers of citations. These DEMP figures were generated by the authors as described in the methods section Brüggmann et al. BMC Women's Health (2016) 16:64 Page 5 of 12 condition [9]. Thus, research in this field needs a strong boost with new and profound funding programs to be initiated by agencies around the world. Since these en- deavors require a sound underlying basis, we identified the need for an all-encompassing depiction of the exist- ing global research landscape and conducted the first de- tailed analysis of worldwide endometriosis research. So far, only a few other OB/GYN topics including breast cancer [7, 27] and smoking and pregnancy [28] were subjected to a similar in-depth analysis using the New- QIS platform. Global endometriosis research is dominated by a small number of scientific power players: These include the USA and the UK holding the leading positions in regards to publication quantity, country-specific citation numbers and h-Indices. Our data align with other stud- ies evaluating the scientific productivity in the biomedical field. Groneberg-Kloft et al. analyzed over 5.5 million Fig. 3 a International collaborations from 1983 to 2009. b Number of co-authors Brüggmann et al. BMC Women's Health (2016) 16:64 Page 6 of 12 publications related to 22 organ systems and identified the USA in the top position regarding overall research output [29]. Comparing our results with other investigations in the areas of Internal Medicine or OB/GYN in particular leads to a similar picture: When scientific productivity was evaluated in regards to “tuberculosis”, bacterial men- ingitis”, “influenza” as well as “smoking in pregnancy ” or “breast cancer ”, the USA and the UK were once again dominating the field [28, 30 –32]. This pattern might point to the fact that both countries dedicate major financial re- sources towards biomedical research creating a supportive scientific infrastructure, e.g. as indicated by the worldwide highest number of endometriosis research institutions (n: 1293) located in the USA. Also, both nations established numerous fruitful collaborations facilitating high quality research. Furthermore, we identified Belgium and Japan as prominent scientific forces within the endometriosis com- munity. Japan’s strong interest in the field might be based Fig. 4 a Number of collaborative items published in a joint effort between two countries dedicated to research in the field of endometriosis. The figure depicts only cooperations of countries with more than 20 collaborative publications b Proportions of international collaborative efforts among all publications of the ten most proliferative countries in endometriosis research Brüggmann et al. BMC Women's Health (2016) 16:64 Page 7 of 12 on the fact that prevalences of endometriosis and asso- ciated clear-cell ovarian cancers are estimated to be the worldwide highest among Asian - and particularly Japanese - women [33, 34]. Therefore, the nation prior- itizes related research with the aim to alleviate the as- sociated disease burden for its inhabitants. For many years, Belgian scientists (e.g. at the University of Leuven) have been focusing on endometriosis research. Their efforts translated into numerous highly regarded publica- tions as documented by the highest country-specific cit- ation rate this nation received in our analysis. Concerning country-specific citation rates, we also found three Scandi- navian countries (Sweden, Finland and Norway) among the five leading nations indicating the outstanding quality and high recognition of their publications. This finding might be linked to the vast data resources these countries Fig. 5 a Distribution of subject area assignments per endometriosis publication. b Most frequently assigned subject areas Brüggmann et al. BMC Women's Health (2016) 16:64 Page 8 of 12 established (e.g. The Swedish National Patient Register), which enable researchers to conduct meaningful and highly cited key studies in the field. The need for an assessment of the worldwide endomet- riosis research architecture becomes even more pressing when the limited number of studies with a global perspec- tive on endometriosis is compared with the fact that this enigmatic disease heavily affects female health in a global context - ranging from high income to low income coun- tries and all ethnicities. In this respect, Nnoaham et al. stressed that little is known about the impact of endomet- riosis across the world [35]. Therefore, they initiated inte- grated multicenter studies to collect prospective, standardized, epidemiological data, to 1) examine the glo- bal impact of endometriosis and relative effect of risk- factors, and 2) develop a symptom-based diagnostic tool [35]. Their studies encompassed 19 hospitals in 13 coun- tries [36, 37]. In one study, the authors assessed the im- pact of endometriosis on mental, physical and social well being and concluded that endometriosis impairs health- related quality of life and work productivity significantly across countries and ethnicities, yet women continue to experience diagnostic delays in primary care [37]. These findings stress the need for further multinational ap- proaches, especially also with the participation of low income countries in which millions of women suffer from undiagnosed and insufficiently treated endometri- osis. This claim is substant iated by our presented data: A closer look into the global endometriosis research architecture exemplifies that a large gap of research ac- tivity exists in a multitude of countries in which – under conservative estimations – tens of millions of affected women live, e.g. in China, India (BRIC countries – nations at a similar stage of newly advanced economic develop- ment - with established research infrastructures that could be instantly used for endometriosis research) and African countries. These numbers are mirrored by an extremely low number of endometriosis publications originating from these countries. This disparity verifies that research in this field is simply not a priority in developing or under- developed countries. Overall, research on the endometri- osis in low resource countries is extremely scarce. Kyama et al. reflected on the problem of endometriosis in women living on the African continent and concluded in 2007 that research programs have to be developed and estab- lished to tackle the local unique challenges the condition creates [38]. The authors point out that rates of endomet- riosis are reported to be lower in African women com- pared with females in industrialized countries. They attributed this finding to an epidemiological under- estimation since the locally perceived need for accurate studies is low, to under-diagnosis due to limited awareness Number of Articles Citation Rate Journal Number of Articles Citation Rates Fig. 6 The 15 most prolific journals in endometriosis research with number of articles, number of citations and citation rate Brüggmann et al. BMC Women's Health (2016) 16:64 Page 9 of 12 of both patients and doctors, restricted access to health- care and surgical resources as well as a protective lifestyle (e.g. earlier childbearing, high parity). Our study further verifies the clear lack of research activity in countries of low-resources and reinforces Kyama ’s call to action in particular. Hence, it would be key to extent the world- wide increasing collaborative efforts and involve these underserved nations with the aim to share data, resources and knowledge. In this context, we have to mention one exception, Kenya, showcasing successful international col- laborative endeavors: This African nation has established 41 co-operations with other countries (e.g. with Belgium). As early as 1968, spontaneous endometriosis was reported in baboons [39, 40]. Since then, these monkeys, which are housed in the “Institute of Primate Research ” in Nairobi (http://www.primateresearch.org), serve as an invaluable animal model in the field of endometriosis research lead- ing to many milestone publications in the field [41 –49]. Several methodological issues need to be discussed when interpreting the present data: 1) As an important strength of this study, the NewQIS platform constitutes an established protocol to assess basic and clinical sci- ences benchmarks in a standardized and verified way. So far, it was primarily used i.e. within the areas of public health [29, 50 –53] and internal medicine [32, 54]. Now, it has been extended to OB/GYN; in this field, many dis- eases are treated that pose a major thread on female and pediatric well-being and have large public health impli- cations. 2) Our platform is configurated to access the WoS database instead of PubMed. Therefore, differences in the overall number of identified endometriosis publi- cations can be expected. This finding can be explained by the differing set of journals enlisted in both databases. However, we prefer to work with WoS as the primary database since it enables the user to integrate a concise citations analysis. This unique feature allowed us to perform valuable multifaceted semi-qualitative ap- proaches, i.e. by calculating endometriosis-specific, country-specific h-indices or average citation rates. 3) A language bias constitutes a mentionable weakness of the presented NewQIS analysis: Clearly, the WoS - but also the PubMed - does not automatically index every Non- English scientific journal. By contrast, other databases such as Scopus include them. Since the majority of jour- nals included in the WoS - and therefore analyzed in our search - are written in English an underrepresentation of non-English publications can be assumed. Especially in the area of public health and epidemiology, which are often focused on country-specific, national issues, there may be non-English endometriosis studies that are not traceable in the WoS. However, we consider this language bias as limited because data of outstanding interest and quality will be published in WoS-listed scientific journals and therefore included in our search.

This is the first study to delineate a picture of the global research landscape of one of the most enigmatic diseases present in OB/GYN. In this area of medicine, the USA plays the leading role for the advancement of science. It is the country with the highest number of highly cited endometriosis publications and it shares the highest num- ber of collaborations with other countries. It is also note- worthy that small Northern European countries such as Belgium, Finland and Sweden, seem to dedicate many re- sources in relation to their low numbers of inhabitants. An intensification of research efforts is needed to battle pressing challenges on a global scale such as the malignant transition of endometriosis or the development of novel non-invasive diagnostic tests and treatment approaches in order to improve disease management for millions of af- fected women in industrialized and developing countries. In this context, it should be a priority of supranational in- stitutions such as the WHO or private funding organiza- tions to provide the much needed monetary support. Additional file Additional file 1: Most cited articles in endometriosis research. The table depicts the ten most cited articles in the area of endometriosis research are displayed including their title, publication year, country of origin, citation count and journal. (DOCX 113 kb) Abbreviations CR: Citation report; DEMP: Density Equalizing Map Projections; HI: Hirsch- Index; NewQIS: New Quality and Quantity Indices in Science; OB/ GYN: Obstetrics and Gynecology; UK: United Kingdom; USA: United States of America; WoS: Web of Science

We thank Gabriele Volante for expert editorial help. This study is part of a thesis project (AEM). Funding We did not receive any funding to conduct this study. Availability of data and materials The datasets supporting the conclusions of this article are available upon request. Authors’ contributions DB, AEM and DAG conceived of the study and designed the experiments, AEM and DK performed the technical conduction of the experiments, DB, AEM, DK, DQ, JJ and DAG analyzed and discussed the results, and drafted the manuscript. All authors read and approved the final manuscript. Competing interests The authors declare that they have no competing interests. Consent for publication Not applicable. Ethics approval and consent to participate Not applicable, because this study did not involve human participants, human data or human tissue. Received: 1 June 2015 Accepted: 10 June 2016 Brüggmann et al. BMC Women's Health (2016) 16:64 Page 10 of 12

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