Bioinformetric Studies on Tuberculosis Vaccines Research. In book: The Art and Science of Tuberculosis Vaccine Development. Edition: Chapter: 22Publisher: Oxford University Press

Topics associated with ethics in TB vaccines and with TB in general have been less dealt with by the international community Untitled – Christopher Püschner Photography ‘Here I want to see those men of hard voice. Those that break horses and dominate rivers; those men of sonorous skeleton who sing with a mouth full of sun and fl int.’ The Laid Out Body (Poem) – Federico Garcia Lorca CHAPTER 22 Chapter-22.indd 441 9/3/2010 12:52:00 PM Christopher Püschner Born in 1958, Christopher Püschner trained in purchasing before studying design at Bielefeld Polytechnic. He has been writing features on political, social, and travel themes in Eastern Europe and the Middle East since 1989, primarily for Stern, Spiegel, Focus, and LIFE; he joined Zeitenspiegel in the summer of 1999. Chapter-22.indd 442 9/3/2010 12:52:07 PM CHAPTER 22 Maria Victoria Guzmán-Sánchez, Humberto Carrillo-Calvet, José L Jiménez Andrade, and Elio A Villaseñor-García Bioinformetric Studies on Tuberculosis Vaccines Research Introduction Th e term Bioinformetrics is used here to refer to the mathematical analysis of the biological documentation contained in digital repositories (local or distributed, in the Internet and in databases) using the resources (concepts, methods, techniques, etc.) of several disciplines (e.g. bibliometrics, informatics, and computer intelligence). In this chapter, scientifi c research since 1950 on the TB vaccine is analysed. Th e study takes advantage of the huge databases on scientifi c research articles at present publicly available in digital format, as well as the new information technologies, enabling automation of certain stages of the analysis process, such as visualizing quantitative results using diff erent geometric representations. Based on the use of bibliometric indicators, the information available on the Internet, and in soft ware systems based on artifi cial networks, the neural networks present study is set within the emergent fi elds of Data Mining (1) and Knowledge Discovery in Data Bases (2). Data on TB vaccine research for the past 57 years were extracted from MEDLINE, the database which is accessible online through the PubMed1 portal. MEDLINE, which contains more than 16 million research papers on biomedical 1 PubMed (http://pubmed.gov/) is the freely accessible online data base of biomedical journal citations and abstracts created by the US National Library of Medicine. One of the more important components of PubMed is the MEDLINE database. Chapter-22.indd 443 9/3/2010 12:52:07 PM 444 The Art & Science of Tuberculosis Vaccine Development subjects and covers about 5,000 diff erent journal titles, constitutes a very rich source of biomedical information. Each scientifi c paper included is indexed according to the US National Library of Medicine’s controlled vocabulary, known as ‘MeSH’ (Medical Subject Headings). MeSH has the complex structure of a hierarchical thesaurus. Th is structure grows in a dynamic way and adapts as the knowledge in the fi eld evolves. For example, for a long period of time the only MeSH term associated with ‘Tuberculosis Vaccines’ was ‘BCG Vaccine’. In 2003, the MeSH term ‘Tuberculosis Vaccines’ was fi nally included in the thesaurus. Following this, the term ‘BCG Vaccine’ became a subcategory of ‘Tuberculosis Vaccines’ in the most updated version of the thesaurus. Th e MeSH terms also describe the contents or topics found in an article. For this reason, the study of MeSH terms with their subheadings and major topics can be considered an indicator of the evolution of knowledge on a topic. Furthermore, knowledge generated (or produced) by research would only be made known when it is published and scrutinized by peer review allowing scientifi c discourse for the generation of new ideas or theories. Th erefore, scientifi c publications can be considered a product of scientifi c activity. Th is approach allows us to use the analysis of research articles under MeSH terms (e.g. tuberculosis vaccines) as an adequate way of characterizing a research topic. We have found that the fi rst papers registered in MEDLINE under the ‘Tuberculosis’ MeSH term appeared in the 1940s and the number of articles up to January 2008 stands at 132,703. MEDLINE reports the fi rst papers related to TB vaccines since 1950 (at that time indexed under the term ‘BCG Vaccine’). All the journal articles included by MEDLINE throughout the period from 1950 to January 2008 will be analysed in the following sections. Th e ViBlioSOM (3) methodology, installed in the ViBlioSOM v.1.0 beta (4) soft ware system, was used to carry out the exploratory analysis of the volume of information contained in MEDLINE. Th is is a neurocomputational technology that uses artifi cial neural networks based on the SOM (Self Organizing Maps) family of algorithms, which is useful for cluster analysis of digital data and the automatic generation of visual representations in the form of maps or cartographies (5). Th is soft ware was created specifi cally for the metric analysis and visualization of digital bibliographic information. Th e analysed data show the sustained interest of the scientifi c community in research related to this disease, as well as important variations in the research patterns during diff erent periods. Since the year 2000, new research lines appeared and fl ourished in the development of TB vaccines. Th e exploratory analysis presented in this chapter is just an example of the type of studies which are made possible by the new technological resources available. It is not an exhaustive study but it is aimed to stimulate further research. Chapter-22.indd 444 9/3/2010 12:52:07 PM 445 Bioinformetric Studies on Tuberculosis Vaccines Research Tuberculosis It is well known that the scientifi c community has devoted a considerable amount of attention to infectious respiratory diseases, but the data found in MEDLINE showed that TB has received special attention. Th e volume of research published on TB since 1950 (131,459 articles) signifi cantly contrasted with the quantity published on other respiratory infections, such as pneumococcal disease (12,609 articles), meningococcal disease (7,997 articles), or legionellosis (4,024 articles). Figure 22.1 presents the pattern on the volume of articles on TB research (TB MeSH count). It can be observed that there have been notable variations during the study period (1950–2007). From an average annual number of 3,438 articles published during the period from 1950 to 1952, there was a gradual decline during the next 10 years (1952–62), down to 1,844 articles in 1962. Later, the quantity increased again, reaching 3,040 articles in 1964. Th e following 10 years (1964–74) showed minor fl uctuations with an average of 2,459 articles annually. Aft er this period, the number of journal articles dropped to 1,797 in 1975, while from 1975 to 1988 the volume of publications stabilized, with small fl uctuations, averaging around 1,528 articles annually. Since 1989, a trend towards sustained growth began (with a non-signifi cant exception in 1997) reaching a total of 3,077 documents in 2007. Th e extrapolation from this continued growth trend indicates that in the following years the Figure 22.1 Evolution of Scientific Production Indicators for TB and TB Vaccines, 1950–2007 4000 3500 3000 2500 2000 1500 1000 500 0 TB TB-Vaccines 1950 1953 1956 1962 1965 1968 1971 1974 1977 1980 1983 1986 1989 1992 1995 1998 2001 2004 2007 1959 Chapter-22.indd 445 9/3/2010 12:52:07 PM 446 The Art & Science of Tuberculosis Vaccine Development highest level of publication production of the whole study period may reach those of 1952. Some specialists in the fi eld have studied and given explanations for the variations in the value of the bibliometric production indicator. For example, it has been considered that the appearance of MTB strains resistant to traditional drugs and the HIV epidemic have motivated new diagnostic and therapeutic research, as well as the urgency for improving BCG and/or for new vaccine development (6–8). It is thought that all these factors have favoured considerable increases in scientifi c publications during the last 20 years, specifi cally on the topic of TB vaccines (Figure 22.2). Tuberculosis Vaccines and Cancer Therapeutics Whereas the production indicator for TB for the 1950–2007 period showed an average of 2,241 articles per year, the corresponding indicator for ‘Tuberculosis Vaccines’ revealed an average of only 254 articles, with a total number of 14,847 articles accumulated during this period (Figures 22.1 and 22.2). Th is last sum is an important part (35 per cent) of the total production under ‘Bacterial Vaccines’ for the period, which amounts to 42,103 articles, and includes 20 diff erent classes of this type of vaccines (Anthrax, Autovaccines, Brucella, Cholera, Diphtheria-Tetanus-Acellular, Pertussis, Diphtheria-Tetanus-Pertussis, Diphtheria-Tetanus, Escherichia coli, Haemophilus, Lyme Disease, Meningococcal, Pertussis, Plague, Pseudomonas, Rickettsial, Salmonella, Shigella, Staphylococca, and Streptococcal). Figure 22.2 Volume of Publications Pattern on TB Vaccines, 1950–2007 1950 1953 1956 1962 1965 1968 1971 1974 1977 1980 1983 1986 1989 1992 1995 1998 2001 2004 2007 1959 600 500 400 300 200 100 0 Chapter-22.indd 446 9/3/2010 12:52:07 PM 447 Bioinformetric Studies on Tuberculosis Vaccines Research In Figure 22.2 we see that the productivity indicator associated with TB vaccines shows a very outstanding peak near the year 1978. Th e search of an explanation for this phenomenon motivated a series of computer experiments carried out to automatically explore the database, using the neural network of the ViBlioSOM soft ware system. Th is neural network has the capacity for Figure 22.3 Mapping of the Main Journal Titles* for the Year 1978 Note: The regions of higher rate of production levels are marked in red and the lower levels in blue (according to the chromatic bar in the lower part of the figure). The journal titles specialized on cancer (see Table 22.1), shown in white letters, concentrate near to regions of high rate of production levels (c.1978). In black letters are shown all the journal titles in which where published a least 21 articles during the period 1950–2007, indexed under ‘Tuberculosis Vaccines’. 1978a Gac Med Mex Przegl Dermatol Acta Derm Venereo Union Med Can Yale J Biol Med Scott Med J Of f entl Gesundheitswe s Br J Dermato Pediatrie Pathol Microbiol (Basel ) WHO Chron Acta Paediatr Scan d Med MonatsschrMinerv a Me d Surgery J Med Ly on J Pediatr Beitr Klin Tuberk Spezif Biull Eksp Biol Me d Lab Inv es t J Indian Med Asso c Br J Cance r Experienti a Pediatr Akus Gineko l Am Rev Respir Di s Dan Med Bull Lijec Vjes n Pediatr Pol Maroc Med Dosw J Reticuloendothel So c Nouv Presse Me d Paediatr Indones Pediatriia Zh Mikrobiol Epidemiol Immunobio R ev Med C ordob a J Immuno l Sov Me d Boll Ist Sieroter Mila n Ann Soc Belg Med J Invest Dermato Qpeqnqi{ Vwoqtk Ann Intern Med Med Trop (Mars) N Engl J Me d Duodecim Arch Roum Pathol Exp Microbio Nurs Times Postgrad Me d Vopr Okhr Materin De t J Med Liban Brux Med Bol Of icina Sanit Pana m Arch Immunol Ther Exp (WarszEur J Pediat r Z Parasitenk d Agents Action s Gut An Esp Pediatr Allergol Immunopathol (Madr) AMB Rev Assoc Med Bra s Public Healt h Am J Me d Acta Lepro l Padiatr Grenzge b "Tcfkcv"Qpeqn"Dkqn"Rj{u Braz J Med Biol Re s ref uah Can Med Assoc J Lab Delo J Assoc Phy sicians Indi a r J Dis Chest Ethiop Med J Cas Lek Cesk Am J Trop Med Hy g Wiad Le k Urol Re s Int J Epidemio Pediatr N Z Med JJ R Soc Me d Urologe A Nippon Gan Chiry o Gakkai Sh Rev Paul Med Zhonghua Wai Ke Za Zh Br J UroCan J Public Healt h BMJ Science RespirationAnticancer Res Southeast Asian J Trop Med Public Healt h Med J Malay si a Przegl Epidemiol Dermatol Venereol East Af r Med J Am J Epidemio Mem Inst Oswaldo Cru z Trans R Soc Trop Med Hy Arch Dis Chil d Rev Clin Es p Vet Rec Can J Uro cp"Vq"Mcicmw"T{qjq Ann Urol (Paris ) Curr Opin Mol Ther BJU Int Eur Respir J Vaccine J Rheumatol Actas Urol Es p Eur J Clin Microbiol Inf ect Di s Rev Inst Med Trop Sao Paul o Clin Exp Immuno Infect Immun J Infect Di s Pcvn"Ecpegt"Kpuv"Oqpqi t Ugokp"Qpeq n Kpv"L"Ecpegt L"Pcvn"Ecpegt"Kpuv Cancer Re s Ogf"Rgfkcvt"Qpeq n Gwt"L"Ecpegt Tgegpv"Tguwnvu"Ecpegt"Tg u Ecpegt"Vtgcv"Tg r Pgqrncuo c L"Uwti"Qpeqn Ecpegt L"Enkp"Qpeqn oowpqn"Koowpqvjg Qpmqnqikg 974a 1973a 1971a 1967a 1966a 1955a 1953a 1951a 1968a 1956a 975a 1972a 1957a 1950a 1954 a 78a 1969a 1952 a 1976a 1970a 1991a 1977a 1963a 1962a 1958a 81a 1961 a 1979a 1959a 980a 1982a 1986a 1989a 1960a 1992a 1964 a 84a 1993a 1995a 1983a 1965a 1985a 2 001a 1987 a 1994a 2003a 88a 1997a 1990 a 1996a 200 2 005a 1998a 1999a 2000a 2002a 2004a 2007 0,0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1,0 Chapter-22.indd 447 9/3/2010 12:52:08 PM 448 The Art & Science of Tuberculosis Vaccine Development classifying the behaviour patterns of the whole group of data obtained from MEDLINE and visually displaying the organization of the diff erent groups of data (technically called clusters) in maps that have the appearance of bidimensional geographic cartographies (Figure 22.3). Th e computational experiments confi rmed a reasonable hypothesis: this conspicuous increment of the research activity level associated with TB vaccines, is due to the emergency of therapeutic cancer research. Th e hypothesis is based in the well-known fact that BCG has a non-specifi c antibody stimulating capacity and confers a general immunogenic power, that has antitumour eff ects useful in the treatment of diff erent types of neoplasms and particularly for bladder cancer (9). In fact, the data analysis that are presented in this section reveal a burst of interest of the scientifi c community’s for studying the therapeutic usefulness of BCG during the decade of the 1970s and the beginning of the 1980s. In order to carry out the computational experiments, we extracted from MEDLINE the collection of journal titles in which articles associated with the ‘Tuberculosis Vaccines’ MeSH term were published; this set of articles is called here TB-Vaccines. Th en the resulting collection of journal titles was mathematically modelled in a multidimensional Euclidean space. According to this model, each journal was represented as a vector point in a mathematical space that has as many dimensions as there are years in the 1950–2007 period; each vector component of the vector associated to a specifi c journal, representing the number of articles of the TB-Vaccines data set that appeared in this journal in that year. Using this model, by means of the neural network of ViBlioSOM, we automatically classifi ed all the journals (2,079 titles) that have published articles that belong to the base TB-Vaccines (14,847 articles), according to their patterns of evolution during the period 1950–2007. A series of maps, that visually represent the evolution of the production in the journals over the years (1950–2007), where also produced with ViBlioSOM. One representative sample of these maps is presented in Figure 22.3. Th is particular map shows the distribution (and concentration) of the articles in the TB-Vaccines base in the diff erent journals during the year 1978. It is clear that the journals specialized on cancer topics (see Table 22.1) stood out among the journals which in 1978 exhibited the highest production levels. Th e maps corresponding to other years circa to 1978 are not presented here since they show a similar behaviour. Th e bar in the lower part of Figure 22.3 chromatically codifi es the proportion of articles published in the diff erent journals. Th is code scales from 0.0 to Chapter-22.indd 448 9/3/2010 12:52:08 PM 449 Bioinformetric Studies on Tuberculosis Vaccines Research 1.0, with 1.0 indicating the maximum annual production of each journal in the 1950–2007 period. Th e red colour indicates those regions of the map where there are located journals that had in 1978 their maximum production level with respect to TB-Vaccines. Dark blue indicates those regions of the map where there are journals that had in 1978 only a small fraction of their maximum number of ‘Tuberculosis Vaccines’ articles produced in the period 1950–2007. To support the validation of our hypothesis and emphasize the results of the data analysis, we present another two graphs (Figures 22.4 and 22.5). In Figure 22.5 we compare the evolution of the total production on ‘Tuberculosis Vaccines’ (red curve) with the evolution (blue curve) of the production on TB vaccines not related to cancer: articles which are not indexed with topic descriptors (MeSH terms) related to cancer. It is to this collection of documents that we refer here using the label TB-Vaccines*. Table 22.1 List of Journals on Cancer British Journal of Cancer Cancer Cancer Immunology, Immunotherapy Cancer Research Cancer Treatment Reports European Journal of Cancer Gan To Kagaku Ryoho. Cancer & Chemotherapy International Journal of Cancer Journal of Clinical Oncology Journal of the National Cancer Institute Journal of Surgical Oncology Medical and Pediatric Oncology National Cancer Institute Monograph Recent Results in Cancer Research Seminars in Oncology Neoplasma Tumori International Journal of Radiation Oncology, Biology, Physics Oncology Note: Collection of journals specialized on cancer in which have appeared articles with the MeSH term ‘Tuberculosis Vaccines’. Chapter-22.indd 449 9/3/2010 12:52:08 PM 456 The Art & Science of Tuberculosis Vaccine Development According to the MeSH, the term ‘BCG Vaccine’ is applied to articles that deal with this topic and the major topic ‘*BCG Vaccine’ when this is one of the main subjects dealt with in the article. Th erefore, it is possible to retrieve two separate databases from PubMed specifi cally related to BCG: 1) Th e *BCG Vaccine (3,762 articles) database, containing articles in which the BCG vaccine was a main topic and is not described by any subheading, 2) Th e BCG Vaccine (6,343 articles) database, containing articles in which BCG vaccine was considered a secondary topic and has associated other MeSH terms or major topics. Analysing the patterns of activity in these databases, it is possible to identify which topics and/or what types of research have been relevant at diff erent times. For example, in Figure 22.10, it can be observed that the evolution of the *BCG Vaccine component has sharp variations during the 1950–1965 period (minimal activity in 1959 and maximum in 1964) and shows two clearly diff erentiated stages: before and aft er 1980, where from 1980 onwards, this type of production has been greatly reduced. On the other hand, the publications contained in the BCG Vaccine database has a radically diff erent development pattern. Figure 22.10 shows the patterns corresponding to BCG Vaccine and *BCG Vaccine. In this fi gure, scientifi c production related to BCG Vaccine has been broken down into two components. One of them BCG Vaccine/*SubH or SubH, is the one containing those articles dealing with BCG vaccine described by some subheading (with or without*), but it is not one of the main topics of the article; the other component, labelled as BCG Vaccine, corresponds to articles that have this MeSH term associated with it in its simple form, that is, not qualifi ed by another subheading. In Figure 22.10, it is possible to see that the BCG Vaccine database appeared in 1965 and also, that 1980 marks an important moment for the type of research it represents. Before 1965, all the publications related to BCG was Figure 22.10 Breakdown of Publications Related to BCG Vaccine into its Components 300 250 200 150 100 0 50 1950 1953 1956 1959 1962 1965 1968 1971 1974 1977 1980 1983 1986 1989 1992 1995 1998 2001 2004 2007 *BCG Vaccine BCG Vaccine/ *SubH OR SubH BCG Vaccine Chapter-22.indd 456 9/3/2010 12:52:09 PM 457 Bioinformetric Studies on Tuberculosis Vaccines Research indexed with asterisks as ‘*BCG Vaccine’, without associated subheadings or as ‘BCG Vaccine/*subH’, meaning that the articles in which the BCG topic has a secondary role (classifi ed as ‘BCG Vaccine’ or ‘BCG Vaccine/subH’) started to appear in this database since that year. Th e major topics (MeSH terms marked with an *) that appear in these articles will be useful for identifying the subjects or research topics related to this vaccine in the article. On the other hand, our exploration has enabled us to see that only a small part of the articles in the *BCG Vaccine database has associated subheadings (with or without *). Th erefore, to identify the research topics that are related in a more signifi cant way with BCG in this database, we only analysed the group of major topics that co-occurred with the term ‘*BCG Vaccine’. In Figure 22.10 it is possible to observe that, since 1980, there is a notable reduction of articles indexed as ‘*BCG vaccine’, but as shall be seen, this decrease is compensated by the articles that have the compound term ‘BCG Vaccine/*SubH’. Since generically, all articles should have associated a major topic or some MeSH term qualifi ed with an asterisk, then Figure 22.10 suggest the following interpretation: from 1965 onwards , the production in which the BCG topic has a secondary role (articles labelled with BCG or BCG/subH) begin and continue appearing. Th erefore, the identifi cation of the major topics that co-occurred with BCG since 1965 will also be of interest for this study. Th e development of the groups of articles contained in these databases can be better studied by dividing the analysis of research behaviour into four periods: 1950–1960, 1960–1965, 1965–1980, and 1980–2007. Below is a summary of the main aspects stemming from this analysis. 1950–1960 At the beginning of the 1950–1960 period there was a high degree of activity, which later progressively decreased. Since during this period only articles from the *BCG Vaccines and BCG Vaccines/*SubH databases coexist (Figure 22.10), analysing the group of major topics associated with ‘*BCG Vaccine’ led us to conclude that the most relevant research activities during this period were related to TB, particularly to disease immunology, prevention, and control. Eighteen studies dealt with lung TB. Interest was displayed towards age group studies, expressed by the descriptors: Infant, Newborn, and Child. Leprosy prevention and control also received attention. At this time the presence of tuberculin related studies was also observed. Th ey became more important with the passing of time, playing a predominant role in the following period, 1960–1980. It is important to point out that there is a considerable contribution of many other major topics that, even though they have low levels of co-occurrence with ‘*BCG Vaccine’ (< 12), have an important eff ect on the total sum (see Table 22.2). Chapter-22.indd 457 9/3/2010 12:52:09 PM 458 The Art & Science of Tuberculosis Vaccine Development Table 22.2 Major Topics Co-Occurring with *BCG, 1950–1960 *Tuberculosis 58 *Infant 57 *Child 56 *Tuberculin 53 Tuberculosis: *immunology 31 *Tuberculosis, Pulmonary 18 *Infant, Newborn 17 Tuberculosis: *prevention & control 16 Leprosy: *prevention & control 15 *Mycobacterium tuberculosis 12 A diff erent situation is observed when the group of subheadings associated with the ‘BCG Vaccine/*SubH’ database are analysed. In the panel in Figure 22.11 it is possible to observe that the global behaviour of this database in the 1950s is determined by a select group of subheadings. During this decade, ‘complications’ plays a dominant role, although it decreased until it disappeared in the 1960s, when this subheading was substituted by ‘adverse eff ects’ in the MEDLINE database that increasingly recovered scientifi c productivity levels up to 2007. Th e subheadings ‘administration & dosage’ and ‘therapeutic use’ Figure 22.11 The Nine Most Frequent BCG Qualifiers, 1950–2007 150 100 50 0 BCG/*SubH 1950 1954 1958 1962 1966 1970 1974 1978 1982 1986 1990 1994 1998 2002 2006 60 50 40 30 20 10 0 1950 1952 1954 1956 1958 1960 1962 1964 1966 1968 1970 1972 1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 *immunology - 712 *adverse effects - 668 *administration & dosage - 613 *therapeutic use - 321 *complications - 250 0 1950 1952 1954 1956 1958 1960 1962 1964 1966 1968 1970 1972 1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 30 25 20 10 5 15 *pharmacology - 188 *history - 86 *standards - 80 *genetics - 26 Chapter-22.indd 458 9/3/2010 12:52:09 PM 459 Bioinformetric Studies on Tuberculosis Vaccines Research exhibited a similar behaviour. In these graphs it can also be observed that between 1950 and 1953, historical studies of the vaccine peaked. 1960–1965 Th e articles contained in the *BCG Vaccine database during this period were the only relevant ones that contributed to the total TB Vaccines production (Figure 22.12). By analysing the group of major topics associated with *BCG, it is possible to identify the research that contributed most to reach the maximum *BCG Vaccine amount of production achieved in 1964. ‘*Tuberculin Test’ and basic research issues represented by the term ‘*Research’ together with ‘*Tuberculosis’ and particularly immunologic issues associated with this disease were prominent. 1965–1980 Th e 1965–1980 period could be considered one of ‘transition’ between the type of research already reported (1950–1965) and the 1980–2007 period, where research is directed towards other topics. During this ‘transition’ stage the most signifi cant components of research come from the *BCG Vaccine and BCG Vaccine databases (Figure 22.10). Th e latter contain the group of articles classifi ed under the term ‘BCG Vaccine’, without any subheading qualifying this keyword. Associated with this group of articles were a group of major topics (the terms marked with *) that described the main subjects dealt with in these articles. Th ese are displayed in Figure 22.13. With respect to the research component corresponding to the *BCG Vaccine database, in Figure 22.12 it may be observed that interests on some previously studied subjects (during the 1950–1965 period) continued to persist. Th e Figure 22.12 The Ten Dominant Topics in the *BCG Vaccine Database, 1960–1980 90 80 70 60 50 40 30 20 10 0 1961 1962 1963 1964 1965 1966 1967 1968 1969 1970 1971 1972 1973 1974 1975 1976 1977 1978 1979 300 250 200 150 100 50 0 1961 1962 1963 1964 1965 1966 1967 1968 1969 1970 1971 1972 1973 1974 1975 1976 1977 1978 1979 *BCG Vaccine *Tuberculin Test - 351 *Child - 168 *Tuberculosis - 180 *Tuberculosis: *prevention & control - 156 *Research - 112 Tuberculosis, Pulmonary: *prevention & control - 108 Mycobacterium bovis: *immunology - 106 Tuberculosis: *immunology - 105 *Infant - 99 Chapter-22.indd 459 9/3/2010 12:52:09 PM 460 The Art & Science of Tuberculosis Vaccine Development emergence of other topics related to the function of the immune system, which, as seen before, will become dominant in the 1980–2007 period (see Figure 22.14), is interesting. Since 1966, prevention and control of pulmonary TB gained relevance in this database and, in a precursory way, ‘Mycobacterium bovis: *immunology’ also notably peaked at the end of the 1965–1980 period. Figure 22.14 The Most Significant Terms in the BCG Vaccine Production, 1950–2007 150 100 50 0 BCG/*SubH 1950 1954 1958 1962 1966 1970 1974 1978 1982 1986 1990 1994 1998 2002 2006 60 50 40 30 20 10 0 1950 1952 1954 1956 1958 1960 1962 1964 1966 1968 1970 1972 1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 *immunology - 712 *adverse effects - 668 *administration & dosage - 613 *therapeutic use - 321 *complications - 250 0 1950 1952 1954 1956 1958 1960 1962 1964 1966 1968 1970 1972 1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 30 25 20 10 5 15 *pharmacology - 188 *history - 86 *standards - 80 *genetics - 26 Figure 22.13 The Ten Dominant Topics in the BCG Vaccines Database, 1965–1980 14 12 10 8 6 BCG Vaccine 150 100 50 0 1963 1966 1968 1970 1972 1974 1976 1978 1980 *Tuberculin Test-95 Tuberculosis: *prevention & control-65 *Hypersensitivity, Delayed-44 *Immunity, Cellular-41 Hypersensitivity, Delayed: *immunology-37 Macrophages: *immunology-33 Lymphocytes: *immunology-29 Tuberculosis, Pulmonary: *prevention & Control-29 *Antigens-27 Tuberculosis: *immunology-26 1965 1966 1967 1968 1969 1970 1971 1972 1973 1974 1975 1976 1977 1978 1979 4 2 0 Chapter-22.indd 460 9/3/2010 12:52:09 PM 461 Bioinformetric Studies on Tuberculosis Vaccines Research 1980–2007 Table 22.3 displays the group of major topics that co-occur with any of the diff erent ways in which BCG vaccine is indexed in MEDLINE during the 1980–2007 period. Th e comparison of the major topics in Table 22.3 with those in Table 22.2 reveals clear diff erences that have a time correlation with facts emerging since the 1980s. Having already observed the new research activities that had peaked at the end of the 1970s, a later analysis enables to appreciate how, since the 1980s, the epidemiologic aspects of TB became more important, correlating with the appearance of the AIDS epidemic and the ensuing TB epidemic. A strong interest can be observed (rising in this last period) in the identifi cation of cases (tuberculin test) and immunologic studies related to the disease and the diff erent mycobacterium that cause it. Table 22.3 Most Significant Terms in BCG Vaccine Publications, 1980–2007 Term *BCG BCG BCG/ *SubH BCG/ SubH Total Tuberculosis, Pulmonary: *prevention & control 40 12 68 120 Tuberculosis: *prevention & control 157 28 22 207 Tuberculosis: epidemiology: *prevention & control 58 15 73 Tuberculosis: *epidemiology: prevention & control 23 23 Tuberculosis, Pulmonary: epidemiology: *prevention & control 22 22 Tuberculosis: *immunology 40 40 Tuberculosis: immunology: *prevention & control 22 57 79 *Tuberculin Test 59 51 115 52 277 Tuberculin: *immunology 39 39 Mycobacterium: *immunology 22 22 Mycobacterium tuberculosis: *immunology 13 18 70 47 148 Mycobacterium bovis: *immunology 72 29 101 Mycobacterium leprae: *immunology 34 34 Leprosy: *prevention & control 23 23 *Bacterial Vaccines 13 12 25 Bacterial Vaccines: *immunology 21 21 Antigens, Bacterial: *immunology 13 42 42 97 T-Lymphocytes: *immunology 39 39 *Immunization 12 12 *Vaccination 60 84 30 174 Chapter-22.indd 461 9/3/2010 12:52:10 PM 462 The Art & Science of Tuberculosis Vaccine Development Our exploration reveals that the subheadings that qualify the term ‘*BCG Vaccine’ are rather unimportant. Th e main subheadings associated with this period’s production are displayed in Figure 22.14. As a result of the analysis of the graphs in this fi gure, the rapid growth of research in immunology stands out with a total of 712 articles. Th e subheadings ‘pharmacology’ and ‘standards’, present since 1966, became more important from 1980. Th e emergence of the more modern term ‘genetics’ takes place at the beginning of the 1990s. However, it only appears, associated with the term ‘BCG Vaccine’ in 26 articles. Evolution of the Research Topics Th e study of the research topics was carried out on the TB-Vaccine* Database (Figure 22.15). In the analysis it was possible to identify that, in general, most contributions to the scientifi c production are related to the search for a vaccine against veterinary TB (‘Tuberculosis Bovine’ or ‘Tuberculosis Avian’). Several authors point out that bovine TB is currently a severe health problem worldwide. Although the causal agent was discovered over a century ago, the control of this disease is still beyond reach of the scientifi c community (25). Spain and UK reported an increase in the incidence of bovine TB (0.42 per cent in 2006, as compared to the previous report of 0.31 per cent). In the UK, during the 1990–2003 period, between 17 and 50 new human cases of MTB Figure 22.15 Activity Levels of Research on TB-Vaccines by Subtopics 120 100 80 60 40 20 0 1950 1952 1954 1956 1958 1960 1962 1964 1966 1968 1970 1972 1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 TB-Veterinary TB-Mucosal TB-V-Therapeutic TV-Subunit TB-Animal Models TB-V-Attenuated TB-V-DNA TB-V-Preclinic TB-V-Clinical Trials TB-Bioinformatic Chapter-22.indd 462 9/3/2010 12:52:10 PM 463 Bioinformetric Studies on Tuberculosis Vaccines Research were reported. Th ese data remind us that an important risk for MTB infection persists in certain population groups (26, 27). Th ose articles that had the MeSH terms ‘Tuberculosis, Bovine’ or ‘Tuberculosis, Avian’ were fi ltered. All the MeSH terms that describe the 2000–2007 articles were extracted from this subgroup; the result is shown in Figure 22.16. Th e analysis of keyword co-occurrence is a well established and widely used bibliometric indicator (28–30). Th e co-occurrence matrix of MeSH terms is organized and represented visually, using the neural network of ViBlioSOM, (see map on Figure 22.16). In this map the MeSH terms are organized according to the similarity of their co-occurrence patterns. Th at is, two MeSH terms that have similar frequencies of co-occurrence (with all the MeSH terms) are localized in the map close to each other. Figure 22.16 Map of the Research Lines Chapter-22.indd 463 9/3/2010 12:52:10 PM 464 The Art & Science of Tuberculosis Vaccine Development TB-Veterinary has focused mainly on immunological, prevention and control, and animal-model studies, as well as on the BCG vaccine itself (Figure 22.15). Aft er the 1990s, as can be assessed in Figure 22.15, new lines of research appear, such as DNA vaccines and Subunit vaccines. However, since 2000, all levels of activity increased and the application of Bioinformatics to this fi eld began. Aft er 2000 there is an increase in the MeSH terms that are not indexed under BCG, that is, research that is completely independent from the usual vaccine topic. Th e growth ratio of all these research lines is very signifi cant: 20 per cent of the total TB-Vaccines* publications from 2000 to 2007 (see Figure 22.9). Research on TB immunization using the mucosal route registers low levels of production (Figure 22.15) with respect to the rest of the topics. It appeared at the beginning of the 1990s as a strategy for the development of new vaccines. Since 1993, several authors have established the advantage of the mucosal pathway over other administration routes (23, 31–33). By 2007, 11 studies related to intranasal administration were reported using diff erent substances, such as: IgE and IgG, type II interferon, and IL-4; the inbred mouse models used were: Balb/c, C3H, C57BL, CBA, and ICR strains. Th e fi rst model was the most used in clinical trials. Even if this strategy of mucosal administration of BCG vaccine is considered a novelty, it is important to point out that since 1968 there are documents that report the interest in understanding the pulmonary response mechanisms against the bacteria (34). Others compared tuberculin sensitivity aft er oral or intradermal vaccination in human trials (35). Th e clinical trial activity has been carried out mainly with the traditional BCG in prevention and control, administration, MTB immunology, and time factor studies, among other aspects. Clinical trials have been reported since 1960 (Figure 22.15). Several of these trials received support from the WHO. Table 22.4 shows the strategies for TB vaccine development in relation to Table 22.4 Articles on Clinical Trial within the TB-Vaccines MeSH Database Descriptor Vaccines & Clinical Trials as Topic Vaccines & Clinical Trials as Topic Phase I Vaccines & Clinical Trials as Topic Phase II Vaccines, DNA 12 2 1 Vaccines, Attenuated 6 1 Vaccines, Inactivated 2 0 Vaccines, Subunit 5 0 Vaccines, Combined 1 0 Vaccines, Conjugate 0 0 Vaccines, Acellular 0 0 Vaccines, Edible 0 0 Chapter-22.indd 464 9/3/2010 12:52:10 PM 465 Bioinformetric Studies on Tuberculosis Vaccines Research Clinical Trials topic, in which diff erent phases of the trials reported in the MEDLINE database are shown. As can be appreciated, the main eff orts have been directed towards synthetic vaccines. Several aspects point towards a rising trend in clinical trials, using both BCG-improved vaccines, as well as vaccines based on novel strategies. Th is increase was refl ected in the activity levels reached using animal models and preclinical studies (Figure 22.15). An increase in the scientifi c publications on these two subjects may be related to a greater interest in effi ciently shift ing basic research to vaccine development. Th e use of Bioinformatics techniques for vaccine research is expected to be a catalysing element for achieving a more eff ective vaccine against the disease, however the production indicator still have marginal values (Figure 22.15). In the search for more elements that may contribute information on the development of new vaccines, we resorted to the data on Figure 22.9, where a small group of articles was not associated to the main BGC vaccine MeSH term. Filtering this segment of the data gave the results presented in Table 22.5 where the main technologies being used in vaccine development can be appreciated. However, when secondary terms associated with vaccines: synthetic, DNA, subunit, and others, were studied it was possible to ascertain that many studies still use the BCG vaccine as a reference. Table 22.5 Articles without BCG Vaccine as a Main Term MeSH Articles BCG Vaccine Vaccines, DNA 186 123 Vaccines, Attenuated 139 123 Vaccines, Inactivated 72 69 Vaccines, Subunit 42 20 Vaccines, Combined 28 26 Vaccines, Conjugate 7 4 Vaccines, Acellular 2 1 Vaccines, Edible 1 0 In Figure 22.17, the related terms ‘Vaccines, Attenuated’ are found in Cluster 1 (C1). Work has been carried out in vaccine candidates, including genetic modifi cations of MTB, as well as studies with respect to immunology, antibody formation, and tolerance and protection studies in animal models. ‘Vaccines, Synthetic’, terms which appear in Cluster 2 (C2), seems to be the most successful strategy (Table 22.5). A group of topics coexists related to it. It is important to point out that the fi rst proposals for the inclusion of synthetic vaccines within the new generation of TB vaccines were dated in the 1980s Chapter-22.indd 465 9/3/2010 12:52:10 PM 472 The Art & Science of Tuberculosis Vaccine Development transmitting it, are the depositories of a heritage that, although intangible, determines the capacity of progress in society and the interest on the topic (41). In this sense, signifi cant changes have taken place in the interest and mobility of the topic that shift ed from developing countries towards developed ones. Th e centredness and level of specialization achieved by the topic has also changed, being presently published in only a small number of journals and generally in English. Th is can be seen in Figure 22.22; from the 1950s till 1977 almost all the publications on TB vaccines were made in a diff erent group of journals from the ones that presently publish them. During this period, the journals that published papers on TB vaccines were those located in the upper part of the fi gure (Cluster 1, C1). In this group, it is possible to fi nd, for example, in 1958 Table 22.6 Substances Used during 28 Years of Research on TB Vaccines 1 BCG Vaccines 10,451 2 Antigens, bacterial 624 3 Tuberculin 534 4 Antitubercular agents 484 5 Tuberculosis vaccines 419 6 Antibodies 419 7 Adjuvants, immunologic 369 8 Bacterial proteins 299 9 Antibodies, bacterial 244 10 Bacterial vaccines 231 11 Pertussis vaccine 199 12 Vaccines, synthetic 196 13 Vaccines, dna 188 14 Immunoglobulin g 186 15 Vaccines, attenuated 139 16 Cytokines 138 17 Epitopes 123 18 Measles vaccine 116 19 Tetanus toxoid 96 20 DTP vaccine 94 21 Freund’s adjuvant 92 22 Diphtheria toxoid 89 23 Smallpox vaccine 84 24 Lipopolysaccharides 76 25 Esat-6 protein 72 * Only those substances, accumulating more than 70 articles with regard to their frequency of use. Chapter-22.indd 472 9/3/2010 12:52:13 PM 473 Bioinformetric Studies on Tuberculosis Vaccines Research the journal Revista brasileira de tuberculose e doenças torácicas (Rev Bras Tuberc Doenças Torac) edited in Brazil in Portuguese, which appeared in 1932. It was followed by the Br Med J (England, 1857–1980) and Arch Tisiol Mal Appar Respir (1955–1969), published in Italian; as well as other Brazilian journals, and those in Polish (Gruzlica) and Russian (Probl Tuberk, Zh Mikrobiol Epidemiol Immunobiol). Figure 22.22 Specialized Sources which Published on TB Vaccines, 1958, 1977, 1997, 2007 Chapter-22.indd 473 9/3/2010 12:52:13 PM 474 The Art & Science of Tuberculosis Vaccine Development Since 1977, the situation began to change and the publication stream moved towards journals appearing in Clusters 3, 6, and 7. It is already possible to observe an interest in journals specializing in immunology and biological standards. Besides, in this period, India showed an outstanding interest, undertaking the publication of several specialized journals. In the fi rst decade of this new century, the articles are concentrated in a small group of journals, mainly in those that are considered of impact,5 such as the International Journal of Tuberculosis and Lung Disease (Int J Tuberc Lung Dis, 1997; it was renamed Tuberculosis (Edinburgh) in 2001), Vaccine (1983), and Infection and Immunity (1970). Th e journals should refl ect the rise in the interest on the TB topic and be in agreement with the international situation. Th is should be expressed as an increase in the diversity of titles or countries involved in the publications and not in a reduction of the titles of journals for countries containing articles on TB vaccine. Likewise, the data convey that research on TB, in these last three years (2005–2007), has focused on more specifi c topics, mainly related to immunologic research, vaccine development, or evaluation of the existing ones (BCG vaccines). It is important to point out that the sources represented here are only those that have a frequency of over 23 articles published in the 57 years that were studied. Th e total number of titles analysed belonged to 130 journals. Conclusion In this chapter, we have applied a technique for the analysis of the information contained in the bibliographic databases of MEDLINE and soft ware systems such as ViBlioSOM, to follow-up the evolution of research on TB vaccines. Th is investigation have contributed data and visual representations useful to observe, in a global way, the dynamics of the production of the scientifi c community in various topics related to TB vaccines. Using this approach, the conclusions below were reached. Th e eff orts devoted to the investigation on TB have been remarkably larger than those dedicated to other infectious respiratory diseases. Th e volume of the research production specifi cally committed to the development of a 5 The Impact Factor is one of the quantitative tools for ranking, evaluating, categorizing, and comparing journals. It is a measure of the frequency with which the ‘average article’ in a journal has been cited in a particular year or period. The annual impact factor is a ratio between citations and recent citable items published. Thus, the impact factor of a journal is calculated by dividing the number of current year citations to the source items published in that journal during the previous two years. (Source: PO Seglen. Why the impact factor of journals should not be used for evaluating research. BMJ, 1997; 314: 497). Chapter-22.indd 474 9/3/2010 12:52:15 PM 475 Bioinformetric Studies on Tuberculosis Vaccines Research generation of TB vaccines, has had important variations during the period of study (1950–2007) that qualitatively correlate well with those of the general research on TB, being the latter quantitatively larger by a factor of ten. Th e variations of the level of production on both, general TB research and TB vaccines, show important variations during the studied period; remarkably in four years (1960–1964) the production on TB vaccines had an increment of 748 per cent. Th ere are various hypotheses to explain some of the strong variations that the production have had. Our study has given support to some of them, the emergency of therapeutic cancer research during the 1970s and other relations cause-eff ect that we refer below (e.g. the pandemic eff ect caused by AIDS in the 1980s). However, there are still other important variations whose underlying causes are yet to be investigated. Th is is the case, for example, of the critical period of 1952–1954 during which the production indicator shows a large depression. As was expected, the data analysis confi rmed that the bulk of TB vaccines research in this period of 58 years has been centred on BCG and issues related to epidemiology, adverse eff ects, prevention and control, as well as administration and dosage. However, the indicators that were used, showed only a marginal level of research on TB vaccines not related to BCG. New strategies and the interest in the search for a new vaccine or the improvement of the existing one begins become relevant only at the end of the studied period. Th e analysis proved that for the last 10 years, there has been a sustained increase in research production on the TB vaccines topic. Th is growth is coincident with the rise in disease cases and the subsequent WHO statement, declaring it a re-emergent disease and a pandemic problem. Th e data also showed several elements that point towards a growth of scientifi c production on the topic for the following years, which might also be an eff ect caused by the need, in a short time interval, of a more eff ective TB vaccine. Among the new research elements found in the data we have observed: Th e use of the new research technologies or strategies, which appear or • have been promoted since the year 2000 and may indicate new directions and changes in the traditional methodology for obtaining vaccines, such as DNA and subunit vaccines. Th e application of Bioinformatics in this fi eld that will allow TB vaccine • research access to a knowledge that will aid in a faster exploration of the MTB genome, and in identifying and testing in human models new vaccine candidates. Th e growing levels of scientifi c production in animal models and preclinical • studies, support the expectation that at some percentage of these studies will achieve success and several vaccine candidates will enter human clinical trials. Chapter-22.indd 475 9/3/2010 12:52:15 PM 476 The Art & Science of Tuberculosis Vaccine Development Ethics has been little dealt with within the TB vaccines and TB topics in general. Ethics focused on TB in general has mainly related to prevention and control of this disease, with special emphasis on HIV/AIDs patients. Th ere is interest in legal questions, as well as in studies to try to improve the understanding of the factors participating in the appearance of disease, their prevention, and elimination. Essentially, in the vaccine topic, the main concerns have been associated with clinical trials, specifi cally in developing countries and in BCG vaccination of immune depressed people (especially HIV-infected ones). Analysing science from the perspective of publications, as an eff ective means of inquiring into the evolution of knowledge, has allowed the observation that the TB vaccines topic has achieved a greater level of homogenization and specialization. Th e eff orts have concentrated on those journals, in which the central topics are more focused on vaccines, immunology, genetics of mycobacteria, and molecular biology. Likewise, there is a polarization of the sources publishing on the topic; of the various countries that contributed with their journals to the mainstream of science, many ceased to exist or stopped being leaders in the topic. At present, publications on TB vaccines are concentrated in a nucleus of 10 journals. Among the journals, 80 per cent of these titles, edited in a non-Anglo-Saxon language, which concentrated all publications on this topic during the fi rst 20 years of this study, had disappeared by the end of the 1980s. Maybe this was motivated by TB being considered a health problem for developing countries; whereas now, with its re-emergence in developed countries, these have shown a greater interest and have absorbed publications on the topic. From the statistical data and the maps, researchers can make their inferences and reach their own conclusions on the knowledge domains accumulated on TB vaccines research. Acknowledgements Th e authors would like to acknowledge the technical assistance of researchers Juan Carlos Ramírez, Armando Acosta, and María Elena Sarmiento from the Finlay Institute. In addition, the authors thank the support of the ‘Macroproyecto de Tecnologías para la Universidad de la Información y la Computación de la Universidad Nacional Autónoma de México’ and the CONACyT Projects: ‘Desarrollo y Aplicación de Tecnologías de Visualización al Análisis Bibliométrico’ and ‘Investigación de Modelos de Neuronas y Redes Neuronales con Aplicaciones a la Minería de Datos’. Chapter-22.indd 476 9/3/2010 12:52:15 PM 477 Bioinformetric Studies on Tuberculosis Vaccines Research Appendix. Controlled Vocabulary of the National Library of Medicine MeSH Terms. Th e MeSH is the National Library of Medicine’s Medical Subject Headings controlled vocabulary of biomedical terms that is used to describe the main subjects or topics of each journal article belonging to MEDLINE. Th e MeSH contains more than 23,000 terms and is updated annually to refl ect changes in medicine and medical terminology. MeSH terms are arranged hierarchically by subject categories with more specifi c terms arranged beneath broader terms. Skilled subject analysts examine journal articles and assign to each the most specifi c MeSH terms applicable, typically 10 to 12. Applying the MeSH vocabulary ensures that the articles in PubMed are uniformly indexed by subject, whatever the author’s words. MeSH Subheadings. MeSH subheadings are qualifi ers of the MeSH terms to help describe more completely particular aspects of a subject. For example, the drug therapy of asthma is displayed as Asthma/drug therapy. Here Asthma is the MeSH term and drug therapy, written with lower case letters, is the associated MeSH subheading. Table 1 Subheadings for the MeSH BCG Vaccine administration and dosage immunology adverse effects instrumentation agonists isolation and purification analysis legislation and jurisprudence antagonists and inhibitors metabolism biosynthesis methods blood microbiology chemical synthesis pharmacokinetics chemistry pharmacology classification physiology complications radiation effects contraindications secretion diagnostic use standards drug effects supply and distribution economics therapeutic use genetics toxicity history veterinary Chapter-22.indd 477 9/3/2010 12:52:15 PM 478 The Art & Science of Tuberculosis Vaccine Development MeSH Major Topic. 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