Trends in genetic literature with the use of flow cytometry

Abstract

Flow cytometry (FCM) has developed rapidly in recent years. It was originally developed in 1968 for counting and analyzing blood cells in the fields of immunology and hematology, and researchers within these fields initiated important refinements of the methodology (1). The current applications of FCM are diverse, as the technique is used in both research and clinical laboratories. FCM offers a rapid, accurate, and highly sensitive analysis of cellular characteristics, including the detection and quantification of antigens in the membranous or cytoplasmic cellular compartments, quantification of DNA/RNA content, and analysis of drug resistance (2, 3). Despite its widespread use, to our knowledge, no studies have investigated the state of the art and global trends related to the use of FCM in genetic research. Scientometrics, which studies scientific information, can detect trends and biases within a given field of scientific research through analysis of its body of scientific literature. Many studies have used scientometrics to assess the characteristics and the future direction of a field of scientific research (4, 5). In this study, we used scientometric techniques to analyze the use of FCM in the field of genetics. We evaluated the overall growth and trends within genetic research that has utilized FCM, focusing on the organisms studied and the types of research conducted. To analyze the importance of FCM in genetic studies, bibliographical production from 1991 to 2007 was used as a quantitative indicator. The survey of the published literature was conducted using the Thompson ISI database with the keywords "flow* cytometr* and genetic* or genotype*." The use of the asterisk in this search indicates that any ending of the word may be accepted, assuring inclusion of that term in the singular and plural forms. The search terms were used in their compound form because the terms "flow cytometry" and "genetic or genotype," when separate, may include works not related to the two interconnected issues. Lastly, we restricted the search period from 1991 to 2007, because the Thomson ISI provide complete abstract only from 1991, moreover, we analyzed paper until 2007 because our search was made in 2008. Publications were selected according to the following criteria: (i) year of publication of the article; (ii) first author country; (iii) journal; (iv) type of organism studied, classified by the following groups: vertebrates (excepted humans), invertebrates, humans, plants, fungi, protists and viruses/bacteria; (v) among publications using human samples, the disease being studied, and (vi) the cellular content studied, including protein, DNA ploidy, small interfering RNAs (siRNA), gene or DNA content. According to our survey, 2,642 articles that met our criteria were published in the period from 1991 to 2007. Correcting for the "natural" increase of the number of publications (4), a significant increase in the number of publications related to genetics using FCM (Pearson's correlation coefficient r = 0.85; P < 0.01) was observed (Fig. 1). The increase of published work that utilizes FCM in the field of genetics may indicate an increase in researchers interested in this field of science. As the number of publications is one of the most widely used measures to quantify the progress and evolution of a field of science, this increase in publication is likely also due to the natural evolution of the technique, including the improvement of cytometers, development of new monoclonal antibodies, larger production of fluorochromes, and many other medical advances (1, 6). Number of publications from 1991 to 2007 in the field of genetics using flow cytometry. The number of papers was standardized by the number of papers in Thomson-ISI database (see details in text). Of the 2,642 total publications, 2,440 were "articles" (e.g. experimental and descriptive), 166 were "review," and 36 were "short communications" (e.g., notes, letters). In total, 92.3% of the genetic studies were practical works, demonstrating that there was practical interest in using flow cytometry. Indeed, many works in different fields have reported that theoretical studies (review papers) are less common than experimental or descriptive ones (4, 7). Nonetheless, review's papers received more attention and frequently are more cited, probably because they summarize relevant information in a scientific field (4). We observed that of the 2,642 total publications involving FCM in genetic research, 878 (33.2%) were written by authors from the USA, 205 (7.7%) were written by authors from Japan, 196 (7.4%) were written by authors from Germany, and 157 (5.9%) were written by authors from England. The large number of publications by authors from developed countries reflects the infrastructure and investment of these countries in research (8). However, the scientific production of Latin-American countries has grown over the last 20 years, mainly in Brazil, Mexico, Argentina, and Chile (9), thus, the authors of theses four countries accumulated 60 (2.2%) publications about FCM in genetic research. Nonetheless, developing countries often encounter difficulties conducting research in areas that need high-technology instruments, such as, those used in the field of genetics. We observed that 875 different journals published articles relating to FCM and genetics. However, only 15 journals obtained a number of publications greater than or equal to 20 works, representing a total of 476 articles, or 18% of the total publications. The journals most highly represented for publishing manuscripts that utilize FCM in the field of genetics are as follows: Blood (59 articles), Cytometry Part A (56 articles), Cancer Res (38 articles), Appl Environ Microbiol (36 articles), J Immunol (33 articles), Proc Natl Acad Sci USA (32 articles), Cancer (32 articles), Theor Appl Genet (31 articles), Clin Cancer Res (28 articles), Am J Clin Pathol (23 articles), Br J Haematol (23 articles), Cancer Genet Cytogenet (23 articles), J Immunol Methods (21 articles), Plant Sci (21 articles), and Infect Immun (20 articles). These results indicate that a wide variety of journals actively publish work in the field of genetics that employ FCM techniques. FCM can be used to study many organisms. Our analysis revealed that the majority of the studies were conducted with human samples, (1,446 articles, 54.7%), followed by other vertebrates (430 articles, 16.2%), plants (319 articles, 12.1%), viruses/bacteria (223 articles, 8.4%), fungi (61 articles, 2.3%), protist (63 articles, 2.3%), and invertebrates (29 articles, 1.1%). This result revealed a strong bias within the literature for human studies; these studies likely used FCM for the detection of human pathology. Although it was observed that the number of articles using human samples for FCM since 1999 has remained relatively constant, at times even displaying a decline, human studies have continued to represent the largest number of publications (see Fig. 2). Percentage of publications in different taxonomics groups studied in genetic research using flow cytometry along years. FCM has traditionally been used to study human biology, stemming from its origin as a technique to count and analyze human blood cells in the 1950s, followed by the study of lymphocytes and immune monitoring in the 1980s (10). However, our analysis revealed a temporal increase of publications in recent years using FCM to study other organisms (Fig. 2), including plants and viruses/bacteria. These results demonstrate the use of FCM by the scientific community to study a diverse set of organisms. We observed that the majority of FCM-related publications studying plants involved variability studies and species comparison (11, 12), whereas in viruses/bacteria, FCM is primarily used to study the topics of pathogenicity and metabolism, among others (13). Of the 1446 articles using human samples, 795 (55%) are related to human diseases (Fig. 3). Within this set, oncology is the most represented topic, with 642 publications (44%). The scientific development in the study of human genetics related to oncology requires that the scientific research is dynamic, informative and a role in the society by promoting the improved diagnoses and treatment of these diseases. FCM allows for the analysis of the integration of cellular events that occurs during the transformation of a normal cell into a malignant cell, a process that is central to the study of cancer (14). Of the publications related to oncology, the most frequently studied cancers were leukemia and lymphoma (107 articles, 17%), breast cancer (77 articles, 12%), and rectal cancer (74 articles, 11%). Number of publications for each of the main types of human diseases studied in genetic research using flow cytometry. Regarding the cellular content that was studied with FCM, 1606 studies (60.7%) were conducted with proteins, 479 studies (18.1%) were conducted with DNA ploidy, 445 studies (16.8%) were conducted with DNA content including genes, and 3 studies (0.1%) were conducted with siRNA; moreover, 109 papers were not possible to classify (absence of abtract). Depending on the organism, we observed a trend in the choice of the cellular content being studied (Fig. 4). In humans, proteins were the predominant choice for research material, whereas the majority of studies using plants involved genetic material, this result was similar to registered by (12). This is likely due to the different research interests relating to each organism. For human studies, there are many areas of interest, including metabolic and cell activity, immune system and therapeutic monitoring, and diagnosis and prognosis of diseases, which are studied by analyzing proteins because they determine cell phenotype (1). In contrast, studies of plants primarily focus on genetic variability, which is important for preservation and species modification (11, 12). However, in any organism, it is possible to study any type of cellular content (DNA, RNA, and protein) (3). Number of papers for each cellular content investigated by flow cytometry per organism studied in genetic research. Here, we present an extensive scientometric survey of publications in the field of genetics that use the method of flow cytometry to demonstrate the present state of the art of this technique. We observed that countries that have published the majority of work within this field have likely done so as the result of an investment in scientific equipment and infrastructure. We also observed a significant increase in the number of published articles in genetics that utilize FCM, and many major journals display an interest in publishing articles on this topic. Because of this growing interest in FCM, we recommend that government agencies in developing countries initiate both financial investments and efforts to train qualified personnel in order to expand and strengthen the use of FCM in genetic research. Although we observed that FCM is primarily used to investigate human biology and disease, this study reinforces the utility of FCM to study other organisms, such as, others vertebrates (e.g., reptiles and birds) and protist (e.g., algae), to provide insights into evolutionary, ecological, and genetic questions related to several species. The authors thank Dr. Thannya N. Soares (UFG), Dr.Vera Saddi (UCG), Dr. Neusa Batista Soares de Melo, and Ítalo Moraes de Magalhães for valuable discussions during the preparation of this manuscript. Valéria Bernadete Leite Quixabeira*, João Carlos Nabout , Flávia Melo Rodrigues*, * Departamento de Genética, Programa de Mestrado em Genética, Universidade Católica de Goiás, Goiânia, Goiás, Brazil, Programa de Doutorado em Ciências Ambientais, Universidade Federal de Goiás, Goiânia, Goiás, Brazil.

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