1. Introduction
Tandem mass spectrometry (MS/MS) as a tool for diagnosing inborn errors of metabolism (IEM) was introduced in the 90s [
1,
2,
3] and recognized as an ethical, safe, simple, and reliable screening test [
4,
5]. In the same decade, tandem mass spectrometry protocols for newborn screening were developed in the USA [
6,
7,
8]. In the 1990s, MS/MS made it possible to detect more than 30 inborn errors in the metabolism of amino acids, fatty acids, and other organic acids [
2]. Further, the number of metabolites analyzed in one cycle consecutively increased [
7,
9]. Over the subsequent decade, laboratories testing for metabolic disorders have implemented tandem mass spectrometry into their newborn screening programs [
10,
11,
12,
13,
14,
15,
16,
17]. Expanded newborn screening (ENBS) using MS/MS has become a mandatory public health strategy in most countries [
18].
IEM constitutes a group of phenotypically and genotypically heterogeneous metabolic disorders caused by gene mutations encoding metabolic pathway enzymes or receptors. Deficiency or changes in the activity of essential enzymes or other proteins in intermediate metabolic pathways lead to the accumulation or deficiency of corresponding metabolites in cells or body fluids, manifesting in a wide range of diseases with clinical heterogeneity, complicating their diagnosis [
18].
IEMs are classified, considering the biochemical nature of the metabolites accumulated in each disease, into disorders related to carbohydrates, amino acids, organic acids, fatty acids, hormones, and cholesterol [
19]. Collectively, they account for more than a thousand individual genetic disorders, resulting in a significant social and financial burden overwhelming families, communities, and health authorities worldwide [
20].
Although these disorders are rare, they are collectively numerous [
21]. There are population differences in the incidence of IEM [
22,
23,
24]. Many IEMs do not have specific clinical signs and are difficult to diagnose using clinical manifestations or routine laboratory tests alone [
22]. IEM typically results in irreversible neurological and psychological impairment and/or disability or death in affected children. Early diagnosis of IEM can significantly reduce the risk of death and may prevent long-term neurological complications [
25,
26]. There are now many reasonably effective treatments available and improved early diagnosis, and treatment can significantly reduce the mortality and morbidity associated with these disorders [
19,
22,
27].
Many genetic diseases, especially inborn errors of metabolism, are rare, so developing a newborn screening test for every disease is impractical. This obstacle was overcome through MS/MS technology [
28]. MS/MS is more sensitive, specific, reliable, and comprehensive than traditional assays. The outdated classical screening methods of one test, one metabolite, and one disease were replaced by a single test, many metabolites, and many diseases approach, first in the USA, Canada, Australia, and European countries (late 20th - early 21st century), then in some Eastern countries. MS/MS also facilitates adding new disorders to newborn screening panels [
6,
13,
14]. The advantages of this detection system are speed, the ability to analyze many different compounds in a single assay, and minimal requirement for assay auxiliary reagents [
2]. The sensitivity and specificity of this method can reach 99% and 99.995%, respectively, for most amino acid disorders, organic acidemias, and fatty acid oxidation defects [
18].
MS/MS opened up the concept of multiple metabolite analysis to detect various metabolic disorders in a single analytical run. Using several analytes to detect biochemical disorders allows for constructing a metabolic profile [
13,
29,
30]. The adverse consequences of false-positive results are negligible regarding the health-economic benefits provided by ENBS and can be minimized through increased education, improved communication, and enhanced technology [
18].
Screening using tandem mass spectrometry diagnoses more IEM cases than classical clinical screening [
31]. Thus, according to Wilcken et al., in a cohort of newborns examined using MS/MS, the prevalence of congenital errors was almost two times higher than in four previous four-year cohorts using clinical screening methods [
15].
Typically, diagnosis of IEM using MS/MS involves the use of a series of confirmatory tests when IEM is suspected. For this purpose, particular guidelines have been developed [
32]. The ENBS program typically uses a two-tier system, classifying results as “borderline” or “diagnostic.” Infants with an initial borderline result are rescreened. Infants with diagnostic or two borderline results are referred for confirmatory testing [
3]. Next-generation sequencing (NGS) is now included in confirmatory testing in many countries [
33,
34].
ENBS entails many interrelated variables that must be carefully assessed and optimized. More reports worldwide are needed to comprehensively evaluate various populations’ possible benefits, harms, and costs [
35]. The impact of the programs has been assessed in terms of screening effectiveness, costs, and clinical outcome [
2,
4,
14,
36,
37]). Screening additional MS/MS-based IEM for 23 IEM was found to approximately double their detection rate compared with conventional methods used in Germany [
39]. The introduction of MS/MS technology has significantly increased the detection of inherited metabolic disorders, including those not previously covered, with predictable improvements in outcomes for some disorders [
40,
41]. Pilot financial data comparing late diagnosis of treatable IEM with early diagnosis using MS/MS and subsequent treatment suggested that expanded screening with MS/MS would result in reduced morbidity and significant savings in chronic disease and critical care annual costs [
42].
According to researchers, MS/MS in IEM screening allows the diagnosis and treatment of diseases before the onset of symptoms and thus represents a preventive medicine strategy [
35,
39,
43]. Cost-effectiveness studies have confirmed that the savings achieved through expanded NBS programs significantly exceed the costs of their implementation [
18]. Screening with tandem mass spectrometry has been found to provide better long-term outcomes for patients aged six years, with fewer deaths and fewer clinically significant impairments [
36].
One of the considerable challenges in neonatal screening today is differentiating the disorders that would benefit most from ENBS using MS/MS, allowing screening programs to be adjusted accordingly [
44].
Evaluating the cost-effectiveness of MS/MS for neonatal screening in low and middle-income countries (LMICs) is particularly important. Khneisser et al. assessed the cost-effectiveness of IEM newborn screening in Lebanon as a model for similar countries. According to Khneisser et al., it can be argued that the direct and indirect costs saved by early detection of IEM are essential enough to justify publicly funded universal screening, especially in LMICs with high consanguinity rates, as illustrated by data from Lebanon. Direct treatment costs were shown to be diminished by half, reaching an average of US
$ 31,631 per case identified. This difference more than covers the cost of starting a newborn screening program [
45].
Improvements in MS/MS technology are why the authors of several studies have presented the detected IEM frequency as higher than in earlier studies [
46,
47].
Nowadays, reports on the current status of neonatal screening traditionally divide the world into five regions (North America, Europe, the Middle East and North Africa, Latin America, and Asia Pacific), assessing the current situation with NBS in each region and analyzing the activities undertaken in recent years [
48]. However, the problem with IEM screening and using MS/MS as a screening tool may vary within each region.
The application of MS/MS for IEM screening can be studied using bibliometric analysis methods. Bibliometric analysis uses mathematical and statistical methods to evaluate the structure, growth, development, and productivity of publications related to a specific topic. Recent advances in large-scale data analysis, advanced visualization techniques, and network analysis provide well-established tools and techniques for analysis and help to understand the structure and mechanisms of the field under study [
49]. A bibliometric review, using scientometric data processing methods, has advantages over a conventional literature review because it allows for identifying critical issues in the field under study and key directions for future research.
Presented bibliometric analysis aims to describe the network structure of the scientific community in the study area at the level of countries, institutional organizations, authors, and sources; their scientific productivity, directions, and collaboration efforts in a given period (1991–2023).
4. Discussion
The last decade of the 20th century was marked by publications proposing MS/MS as a new screening tool for inherited metabolic diseases, including neonatal screening. The first publication revealing the potential of MS/MS in the field of screening was the publication of a short report by Millington et al. in the Proceedings Papers of the 1989 Annual Meeting of the Society for the Study of Inborn Errors of Metabolism (not included in the present study) [
70]. The first article in the sample under review, published in 1991, analyzing diagnostic markers of genetic disorders in human blood and urine using tandem mass spectrometry, was also by Millington et al. [
53]. The first papers on using MS/MS in IEM screening were published in the USA. At the first stage of publications in this area, which corresponds to the 90s of the 20th century, and at the second, in the 21st century, the leadership of the United States is undeniable (
Figure 4B).
Pilot studies of MS/MS use for newborn screening were first initiated in the USA, in Pennsylvania, Ohio, North Carolina, and Louisiana in 1992-1999 [
71]. A pilot project using universal tandem mass spectrometry for newborn screening began in North Carolina in 1997 to determine the frequency and feasibility of screening for fatty acid oxidation disorders, organic acids, and selected amino acids [
3]. As of 1998, twenty-six US states used MS/MS to screen for IEM in newborns [
38], and this moment corresponds to the surge in publications in 1997-1999 (
Figure 3A,B). However, it is worth noting the involvement of Saudi Arabia in the use of MS/MS as a screening tool (
Figure 4A,
Table 1), which was especially evident at an early stage in the 90s, owing to the publications of Rashed et al. [
1,
72,
73,
74]. Involvement at the level of countries, institutional communities, and individual authors in the problem under study is undoubtedly determined by the current capabilities, including financial and technical ones, and the need to use the IEM diagnostic method. Thus, Saudi Arabia’s involvement may be due to the significance of increasing the frequency of IEM in the Middle East region due to the high degree of consanguinity and the country’s financial capabilities to implement screening programs for IEM using MS/MS [
61,
68,
75,
76].
The US leadership in the field of IEM screening using MS/MS is implicated by differences in approaches to the number of diseases included in the neonatal screening panel and, in general, differences in the pace of screening programs in the USA and other countries, including Europe. In Europe, initially, only certain diseases were recommended for inclusion in the neonatal screening panel for MS/MS, such as phenylketonuria (PKU), glutaric aciduria type 1 (GA1), and medium-chain acyl-coenzyme A dehydrogenase deficiency (MCAD) [
4,
12,
14,
38]. In Great Britain, at the beginning of the 21st century, laboratories routinely used MS/MS to screen for phenylketonuria, and only laboratories participating in the 2-year pilot study screened for MCAD. In general, the ability of MS/MS to detect other IEMs was questioned [
77]. In the analyzed articles’ texts, “Phenylketonuria,” “CoA dehydrogenase deficiency,” and “Medium-chain acyl-CoA” were among the most frequently used original (
Figure 14A,C) and additional keywords (
Figure 14B,D). In Germany, the number of IEMs subject to screening was limited compared to the US during that period. On the contrary, an extensive range of IEM was recommended in the USA, including rare ones or those with unproven clinical significance [
57]. In the USA, MS/MS has been widely used for newborn screening for up to 55 abnormal biochemical conditions, while in Germany, the UK, and Switzerland, for the limited detection of only a few diseases [
9,
78].
Australia should also be considered a leader in the use of MS/MS in IEM screening (
Figure 4A,
Table 1), which is especially significant at the first stage of the MS/MS introduction in neonatal screening, in the 90s of the 20th century (
Figure 4B). The University of Sydney tops the list of significant affiliations (
Figure 7A,B). Australia’s leading position is mainly due to the high citation rates of B. Wilcken’s papers (
Table 2), in particular, Wilcken et al. [
15], which ranks first in the list of the 15 most cited articles on the topic under study and has the highest Total Citation index 483, average citations per year (TC per Year) 23.0, and Local Citations 130 (
Table 4).
MS/MS technology has offered a new vision for newborn screening programs, allowing the detection of dozens of metabolic abnormalities in a single test from a single small spot of dried blood. In the first decade of the 21st century, after several million newborns worldwide were screened and more than 500 cases of inherited metabolic diseases were identified, screening newborns with MS/MS has proven its advantages as a clinical screening technology [
13,
29]. This marked a new phase in the use of MS/MS for IEM screening, and the early 2000s saw a sharp rise in the number of studies on this topic (
Figure 3A,B). Undoubtedly, a significant contribution, especially at the initial stage, to the promotion of the use of MS/MS in IEM screening was made by publications in the field of clinical and analytical chemistry and clinical biochemistry (
Figure 2) [
1,
30,
56,
79], published in the journals Clinica Chimica Acta, Clinical Biochemistry, Analytical Chemistry, included in the 15 most relevant journals that published papers on the topic under study (
Table 3) and in 8 journals that formed the first zone according to Bradford’s Law (
Figure 11A).
Newborn screening deals with rare diseases and its benefits cannot be easily demonstrated without extensive studies [
80]. The adoption of national neonatal screening programs has resulted in the publication of study results [
10,
15,
16,
31,
59,
81,
82,
83,
84,
85], case reports [
86,
87,
88], systematic reviews and meta-analyses [
89,
90], and expert reports and opinions [
38,
91,
92,
93], development of methodological recommendations [
94,
95,
96] and clinical guidelines [
32,
94]. Many papers on the topic under consideration have high rates of global and local citations (
Table 4,
Figure 13A,B). Interest in using MS/MS for IEM screening continues to increase, with publications and citations peaking in 2020 (
Figure 3A,B).
National newborn screening programs based on MS/MS and other newborn screening technologies show significant variation in the screening panel’s number and types of diseases [
31,
35]. Pilot neonatal screening programs using MS/MS have been launched in Europe [
2,
31,
97,
98], Australia [
10,
15], Asia - Japan [
59], Korea [
60], China [
85,
99], Taiwan [
84] already at the end of the 20th – beginning of the 21st century.
The implementation of MS/MS in neonatal screening programs in a significant part of developed countries was completed in the 2010s in Europe - in Germany [
35,
100], Austria [
98,
101], Italy [
41,
102,
103], Spain [
104], Portugal [
105], Denmark [
31], in Asia - Taiwan [
84,
106] and Singapore [
107].
Currently, neonatal screening programs for MS/MS are actively implemented in European countries: Germany [
108,
109], Slovenia [
25,
34,
110], Italy [
111,
112], Spain [
113], as well as in China [
46,
47,
114,
115,
116,
117,
118,
119,
120] (
Figure 4A,B). The outcome of these programs is to estimate the incidence of various IEMs in newborns and the geographic distribution of these disorders. The incidence varies within different racial and ethnic groups, with the predominance of one or another IEM in certain groups [
25]. Differences in the frequency of certain IEMs determine the inclusion of different IEMs in national screening panels [
19,
23,
119,
121]. This, in turn, determines differences in the relevance and frequency of using different keywords in different regions, countries, and periods (
Figure 14C,D and
Figure 15A,B).
In China, the most common hereditary diseases, especially in newborns/infants, are hyperphenylalaninemia (HPA), citrine deficiency, primary carnitine deficiency (PCD), methylmalonic acidemia (MMA), and multiple-CoA dehydrogenase deficiency (MADD) [
19,
115,
117]. MMA has been frequently detected in Japan, China, and India. ENBS found differences in overall IEM rates across countries: 1:8,557 in Japan, 1:7,030 in Taiwan, 1:13,205 in South Korea, and 1:2,200 in Germany. Frequently detected diseases included propionic acidemia (PA) and PKU in Japan, 3-methylcrotonyl-CoA carboxylase deficiency (MCCD) and PKU in Taiwan, MCCD and citrullinemia type I citrullinemia I (CIT I) in South Korea, as well as PKU and MCAD in Germany.
Thus, the incidence rate of IEM varies among countries. Moreover, the disease spectra of inherited metabolic diseases (IMD) detected by selective screening differ from those detected by expanded newborn screening [
23]. The overall incidence of fatty acid oxidation disorders (FAOD) in Asians is much lower than in Caucasians. The significant prevalence and apparent benefit of ENBS for MCAD screening has only been demonstrated in countries with a high percentage of Caucasians [
93]. This determines the focus of individual countries, organizations, and authors on the development of diagnostics of some IEM groups relevant to them and the formation of collaborations between authors (
Figure 10A,B), organizations (
Figure 8A,B), and countries (
Figure 5A,B and
Figure 6A,B) based on these interests.
It is noteworthy that even within the same country, the degree of formation and development of neonatal screening programs may vary. In China, the spread of MS/MS technology in neonatal screening in some regions, particularly the North [
122], Midwest [
85,
123], and Hong Kong [
85,
124], was implemented later than in other parts of mainland China.
In some countries, selective screening programs for IEM using MS/MS have been implemented concurrently with expanded newborn screening. This IEM screening strategy has been actively used in China [
87,
88,
125,
126,
127], Korea [
60], Slovenia [
25,
34,
110], India [
64], Turkey [
21], and Egypt [
128].
It should be noted that there are some financial issues with carrying out ENBS using MS/MS, in particular, in South-Eastern European countries [
129]. In India, financial constraints in the health care system have prevented the implementation of a full-scale enhanced neonatal screening program. Pilot studies using MS/MS to assess the prevalence of IEM have been initiated in Andhra Pradesh as early as 2004 [
64,
130], and selective screening for IEM in India continues to this day [
131,
132]. There is a high prevalence of IEMs, but more extensive studies are required to estimate their true prevalence in India. One of the problems associated with IEM screening programs in India is the lack of international collaboration in conducting research and publishing its results, as reflected by the high SCP (Single Country Publication) and zero MCP (Multiple Countries Publication) (
Figure 5B) and lack of representation India on the international cooperation visualization map (
Figure 6A,B).
Many developing countries do not yet have national neonatal screening programs [
63]. In most developing countries, there are financial challenges to implementing expanded neonatal screening programs. Pilot programs with limited observations or selective screening programs are being implemented in these settings. Pilot programs for expanded newborn screening have been implemented in Turkey [
76] and Malaysia [
133]. Some progress in government support and expansion of neonatal screening programs has recently been achieved in India [
134]. Training in genetic counseling has been expanding in Asia and Africa [
63].
An expanded neonatal program requires an expanded infrastructure for interpreting findings, reporting, treatment, and counseling [
38]. Well-organized logistics of the screening program, from the screening laboratory to central clinical management, are essential [
31]. This may be why there is little information about newborn screening efforts in Nepal, Cambodia, Laos, and Pacific Island countries, and no organized screening efforts are reported from there. As approximately half of the world’s births occur in the Asia-Pacific region, it is necessary to continue ongoing efforts to introduce and expand screening programs there so that children can achieve the same health status as children in more developed parts of the world [
135].
A series of selective screening programs have been implemented in Egypt [
67,
68], Saudi Arabia [
75], and Morocco [
136]. In countries with high rates of consanguineous marriage, the incidence of many IEMs is significantly higher than in countries without such a problem [
61,
68,
76]. Pilot studies performed in some Middle Eastern countries show that the incidence of inborn metabolic disorders is higher in the region than anywhere else in the world due to consanguinity. This problem is relevant in Bahrain [
62], Turkey [
21,
76], Egypt [
67,
68], Saudi Arabia [
75], Lebanon [
45], India [
132,
134], and Oman [
61]. Using authors’ and additional keywords in visualization maps confirms a relatively high frequency of the term “consanguinity” (
Figure 15A - green cluster,
Figure 15B - orange cluster).
Analysis of authors’ and additional keywords, as well as keywords extracted from the articles’ abstracts and titles included in the current study, indicates their multiplicity, which is associated with both the wide range of IEMs and the rarity of IEMs in general (
Figure 14A,B and
Figure 15A,B). Keywords show changes in frequency of use associated with time trends (
Figure 14C,D and
Figure 15A,B), which is related to changes in the relevance of individual keywords, reflecting different directions in using MS/MS as an IEM screening tool over different periods.
One of the current trends in IEM is the development of new or improved diagnostic and treatment methods. The clinical effectiveness of MS/MS screening is unquestionable in some conditions but absent in others. The assessment of rarer diseases is more complex [
20,
137]. Next-generation sequencing in the form of whole exome and whole genome analysis is now strongly proposed as a potential alternative to mass spectrometric screening of newborns for IEM [
20,
138,
139,
140]. These methods have the advantages of high throughput, high accuracy, and the potential ability to detect all types of genetic disorders, even beyond IEMs, with almost equal sensitivity and specificity. However, major limiting factors include data interpretation dilemmas and the relatively high cost of such methods. As an alternative, a combination of MS/MS and sequencing is proposed [
114,
116,
127,
141,
142]. This trend is reflected in the increasing frequency of use the term “next-generation sequencing,” as shown by visualization maps of the occurrence of keywords (
Figure 15A - blue cluster,
Figure 15B - red cluster), a graph of the evolution of authors’ keywords (
Figure 15B) and a three-field graph, reflecting the relationship between authors, author keywords and sources (
Figure 16D). Besides, the frequency of use the term “molecular genetics” in publications on MS/MS in IEM screening, has increased in recent years (
Figure 15A).
One option for using MS/MS for IEM selective screening is the retrospective analysis of dry blood spots (DBS) stored after neonatal screening. This option is used in developing countries with financial constraints, and expanded newborn screening using MS/MS is impossible. In this regard, the issue of storing stains and their storage conditions is being studied. Among the papers on this topic are those from Asia because storage conditions for DBS in hot and humid climates are critical [
134,
143]. However, the issue of storage conditions for DBS and the development of references and correction factors for metabolites is relevant not only for developing countries due to recent trends in the creation of biobanks and using stored samples for metabolomic studies, including disease prediction and understanding the basic molecular mechanisms of disease development [
144,
145,
146].
Thus, different regions and countries are currently at entirely different stages regarding using MS/MS in neonatal IEM screening. Some countries do not provide any data on screening for IEM, as research in this direction has not been carried out (
Figure 4A). Developed countries have undergone pilot and experimental studies, and neonatal screening using MS/MS is now part of their national health programs.
Expanding screening programs has resulted in high heterogeneity in the IEMs included in different ENBS programs. In this regard, two unified screening panels have been proposed by competent organizations in the USA and the European Union [
147]. Currently, attention in developed countries is focused on the special considerations and limitations of newborn screening in sick and premature infants and some of the ethical issues associated with newborn screening. New disorders being considered for testing and new technologies that may be used for newborn screening are also discussed [
116,
148,
149]. New therapeutic modalities, such as enzyme replacement therapy and substrate reduction therapy, are being developed for many inborn errors of metabolism [
20].
Some countries are at the stage of introducing MS/MS screening into public health programs. Some low-income countries have piloted expanded newborn screening programs or sporadic selective screening programs for IEM. In Latin America [
96,
150,
151,
152,
153,
154], some countries in Africa [
67,
68,
136], the Middle East [
45,
62,
75,
76], and the Asia-Pacific region [
24,
133,
135,
155], there are some pockets of activity where new NBS programs are designed by partnerships between governments, non-governmental organizations, academia, the private sector, and civil society [
156].
Thus, the performed bibliographic analysis highlighted substantial unevenness in the development of screening programs based on MS/MS on a global scale. However, the data obtained made it possible to identify the main directions for future screening technologies to detect inherited metabolic diseases. These positive aspects of the study can be referred to as undoubtful advantages. To our knowledge, we are the first researchers who tried to analyze the current bibliography on MS/MS neonatal screening at such a comprehensive level across countries, institutions, authors, journals, papers, and keywords.
Along with that, the study had inevitable limitations:
We used only the core WOS collection to search for relevant sources. The current study did not consider other databases, such as Scopus and MEDLINE. WOS is the most commonly used database in scientometrics, and Biblioshiny and VOSviewer have identified a format for recording metadata from WOS.
Only articles in English were included.
Proceeding papers, book chapters, meeting abstracts, editorial materials, early access articles, letters, and notes were not included in the study.
The total citation rate for newer articles is lower, which can be considered a manifestation of the methodological weakness of the bibliometric analysis. However, this is covered by the average citation indicator per period (year).
Bibliometric and scientometric analysis of articles indexed in the WOS database focused only on metadata, not their content. Analysis of the full text of the included articles and their scientific content was not the purpose of the research as being beyond the scope of this article. Besides, analyzing the textual content of the abstracts was also not the purpose of our study. Article metadata were sources of information about authors and their countries/institutions to assess their productivity, collaboration, and keyword trends.
The textual content of some images displayed by Biblioshiny and VOSviewer is incomplete.
Figure 1.
The flow chart of the screening process using PRISMA.
Figure 1.
The flow chart of the screening process using PRISMA.
Figure 2.
Web of Science Categories.
Figure 2.
Web of Science Categories.
Figure 3.
(A,B) Dynamics of publications (A) and citations (B) on using MS/MS for IEM screening from 1991 to 2023 *. *The upper part of the figures shows polynomial regression models.
Figure 3.
(A,B) Dynamics of publications (A) and citations (B) on using MS/MS for IEM screening from 1991 to 2023 *. *The upper part of the figures shows polynomial regression models.
Figure 4.
(A,B) Countries’ scientific production (A) and performance over time (B)..
Figure 4.
(A,B) Countries’ scientific production (A) and performance over time (B)..
Figure 5.
(A,B) Collaboration network on a world map* (A) and Corresponding authors’ countries (B). *The dark blue color indicates a higher level of cooperation; the broader the line of communication, the higher the level of collaboration between two countries.
Figure 5.
(A,B) Collaboration network on a world map* (A) and Corresponding authors’ countries (B). *The dark blue color indicates a higher level of cooperation; the broader the line of communication, the higher the level of collaboration between two countries.
Figure 6.
(A,B) Cooperation of the leading countries. Distribution of co-authors’ collaborations by countries of their origin. Countries with more than three publications by clusters (A). The number of documents from collaborating countries and their average citations (B).
Figure 6.
(A,B) Cooperation of the leading countries. Distribution of co-authors’ collaborations by countries of their origin. Countries with more than three publications by clusters (A). The number of documents from collaborating countries and their average citations (B).
Figure 7.
(A,B) Most relevant affiliations (A) and affiliations’ performance over time (B).
Figure 7.
(A,B) Most relevant affiliations (A) and affiliations’ performance over time (B).
Figure 8.
(A,B) Maps of institutions’ cooperation. Collaboration between organizations in terms of co-authorship by clusters (A). Connection between the formed 6 clusters of organizations based on the “Citation” indicator (B).
Figure 8.
(A,B) Maps of institutions’ cooperation. Collaboration between organizations in terms of co-authorship by clusters (A). Connection between the formed 6 clusters of organizations based on the “Citation” indicator (B).
Figure 9.
(A,B,C) Authors’ Productivity Analysis. Most locally cited authors (A); Authors’ production over time* (B); and Author productivity by Lotka’s law. *The color intensity is proportional to the total citations per year. The bubble size is proportional to the number of documents. The line represents an author’s timeline.
Figure 9.
(A,B,C) Authors’ Productivity Analysis. Most locally cited authors (A); Authors’ production over time* (B); and Author productivity by Lotka’s law. *The color intensity is proportional to the total citations per year. The bubble size is proportional to the number of documents. The line represents an author’s timeline.
Figure 10.
(A,B) Distribution of co-authors’ collaborations. Cluster analysis of collaboration between authors with more than three publications (A). Collaboration between authors by the “Citation” dimension created in Vosviewer (B).
Figure 10.
(A,B) Distribution of co-authors’ collaborations. Cluster analysis of collaboration between authors with more than three publications (A). Collaboration between authors by the “Citation” dimension created in Vosviewer (B).
Figure 11.
(A,B) Core sources by Bradford’s Law (A) and sources’ productivity over time (B).
Figure 11.
(A,B) Core sources by Bradford’s Law (A) and sources’ productivity over time (B).
Figure 12.
(A,B,C) Journal Collaboration Maps. Collaboration map of journals that have published at least three articles studying the use of MS/MS in IEM screening (A); Interactions between journals based on citations of papers published in them on the topic under consideration (B); Co-citation relationships between journals (C).
Figure 12.
(A,B,C) Journal Collaboration Maps. Collaboration map of journals that have published at least three articles studying the use of MS/MS in IEM screening (A); Interactions between journals based on citations of papers published in them on the topic under consideration (B); Co-citation relationships between journals (C).
Figure 13.
(ABCD.) Analysis of citation. Visualization map of total citations for articles on MS/MS in IEM screening1 (A). Most local cited documents (B). Visualization map of co-citations for articles on MS/MS in IEM screening2 (C). Visualization map of bibliographic coupling of articles on MS/MS in IEM screening3 (D). 1The minimum number of total citations is 50; 84 articles that meet this condition are included. The size and color of the item (node) correspond to the number of total links. 2Clusters are identified by color, with node sizes corresponding to the number of local document citations. The distance and thickness of the lines between items (nodes) show the strength of the connection between documents according to the “Co-citation” parameter and correspond to the number of documents citing them together. 3The minimum number of total citations for a document is 30; 147 articles that meet this condition are included. Clusters are identified by color (8), the sizes of the items (nodes) correspond to the number of total citations, the distance between them and the thickness of the lines show the strength of the connection between documents according to the “Bibliographic coupling” parameter and correspond to the number of matching links in the papers.
Figure 13.
(ABCD.) Analysis of citation. Visualization map of total citations for articles on MS/MS in IEM screening1 (A). Most local cited documents (B). Visualization map of co-citations for articles on MS/MS in IEM screening2 (C). Visualization map of bibliographic coupling of articles on MS/MS in IEM screening3 (D). 1The minimum number of total citations is 50; 84 articles that meet this condition are included. The size and color of the item (node) correspond to the number of total links. 2Clusters are identified by color, with node sizes corresponding to the number of local document citations. The distance and thickness of the lines between items (nodes) show the strength of the connection between documents according to the “Co-citation” parameter and correspond to the number of documents citing them together. 3The minimum number of total citations for a document is 30; 147 articles that meet this condition are included. Clusters are identified by color (8), the sizes of the items (nodes) correspond to the number of total citations, the distance between them and the thickness of the lines show the strength of the connection between documents according to the “Bibliographic coupling” parameter and correspond to the number of matching links in the papers.

Figure 14.
(ABCD.) Analysis of authors’ keywords. Most frequent authors’ keywords (A). Most frequent additional keywords (B). Word frequency in authors’ keywords over time (C). Frequency of keywords plus over time (D).
Figure 14.
(ABCD.) Analysis of authors’ keywords. Most frequent authors’ keywords (A). Most frequent additional keywords (B). Word frequency in authors’ keywords over time (C). Frequency of keywords plus over time (D).
Figure 15.
(AB.) Trending topics of authors’ keywords (A). The evolution of the authors’ keywords (B).
Figure 15.
(AB.) Trending topics of authors’ keywords (A). The evolution of the authors’ keywords (B).
Figure 16.
(ABCD.) Keywords’ co-occurrence maps and relationships between authors, keywords, and sources. Сo-occurrence maps of the authors’ and additional (plus) keywords1 (A). Сo-occurrence maps of the authors’ and additional keywords (plus) after removing some keywords from the list2 (B). Map of the occurrence of keywords extracted from the articles’ titles and abstracts after removing some keywords from the list3 (C). Three-field graph of relationships between authors, authors’ keywords, and sources (journals) (D). 1Minimal frequency of occurrence 5. Seven clusters, 140 keywords. The item (node) size corresponds to the frequency of occurrence; the distance between nodes and the thickness of the lines show the strength of the connection between keywords according to the “co-occurrence” parameter and corresponds to the number of conjoint utilizing. 2Deleted keywords: Tandem mass-spectrometry, mass spectrometry, Inborn errors of metabolism, inborn error of metabolism, Inborn errors of metabolism (IEM), metabolic disorders, inborn errors, inherited metabolic diseases screening). Minimal frequency of occurrence 5. Seven clusters, 128 keywords. 3Deleted keywords: Tandem mass-spetrometry, mass spectrometry, Inborn errors of metabolism, inborn error of metabolism, Inborn errors of metabolism (IEM), metabolic disorders, inborn errors, inherited metabolic diseases screening). Minimal frequency of occurrence 20. Three clusters, 95 keywords.
Figure 16.
(ABCD.) Keywords’ co-occurrence maps and relationships between authors, keywords, and sources. Сo-occurrence maps of the authors’ and additional (plus) keywords1 (A). Сo-occurrence maps of the authors’ and additional keywords (plus) after removing some keywords from the list2 (B). Map of the occurrence of keywords extracted from the articles’ titles and abstracts after removing some keywords from the list3 (C). Three-field graph of relationships between authors, authors’ keywords, and sources (journals) (D). 1Minimal frequency of occurrence 5. Seven clusters, 140 keywords. The item (node) size corresponds to the frequency of occurrence; the distance between nodes and the thickness of the lines show the strength of the connection between keywords according to the “co-occurrence” parameter and corresponds to the number of conjoint utilizing. 2Deleted keywords: Tandem mass-spectrometry, mass spectrometry, Inborn errors of metabolism, inborn error of metabolism, Inborn errors of metabolism (IEM), metabolic disorders, inborn errors, inherited metabolic diseases screening). Minimal frequency of occurrence 5. Seven clusters, 128 keywords. 3Deleted keywords: Tandem mass-spetrometry, mass spectrometry, Inborn errors of metabolism, inborn error of metabolism, Inborn errors of metabolism (IEM), metabolic disorders, inborn errors, inherited metabolic diseases screening). Minimal frequency of occurrence 20. Three clusters, 95 keywords.

Table 1.
Most cited countries.
Table 1.
Most cited countries.
Country |
Total Citations |
Average Article Citations |
USA |
6,057 |
54.60 |
Germany |
1,486 |
53.10 |
Australia |
1,266 |
70.30 |
China |
1,236 |
16.30 |
Saudi Arabia |
971 |
69.40 |
Italy |
616 |
28.00 |
Austria |
577 |
57.70 |
United Kingdom |
562 |
37.50 |
Netherlands |
379 |
42.10 |
Japan |
279 |
18.60 |
Table 2.
Most relevant authors.
Table 2.
Most relevant authors.
Rank |
Author |
Articles / % of 451 |
Articles Fractionalized |
Total number of citations |
H- index |
G- index |
M- index |
Publishing since |
1 |
Matern D. |
14 (3.104%) |
2.72 |
865 |
11 |
14 |
0.5 |
2002 |
2 |
Hoffmann G.F. |
13 (2.882%) |
1.65 |
1,024 |
12 |
13 |
0.545 |
2002 |
3 |
Vockley J. |
13 (2.882%) |
2.27 |
528 |
10 |
13 |
0.455 |
2002 |
4 |
Wang Y. |
12 (2.661%) |
1.66 |
136 |
5 |
11 |
0.294 |
2007 |
5 |
Chace D.H. |
11 (2.439%) |
4.45 |
1,103 |
11 |
11 |
0.333 |
1991 |
6 |
Wilcken B. |
10 (2.217%) |
1.68 |
1,372 |
10 |
10 |
0.455 |
2002 |
7 |
Chien Y.H. |
9 (1.996%) |
0.83 |
610 |
8 |
9 |
0.444 |
2006 |
8 |
Hwu W.L. |
9 (1.996%) |
0.85 |
621 |
9 |
9 |
0.5 |
2006 |
9 |
La Marca G. |
9 (1.996%) |
1.82 |
625 |
8 |
9 |
0.471 |
2007 |
10 |
Mak C.M. |
9 (1.996%) |
1.10 |
185 |
6 |
9 |
0.462 |
2011 |
Table 3.
Most relevant journals.
Table 3.
Most relevant journals.
Rank |
Journal |
N of Publications / % of 451 |
Total N of citations |
H-index |
G-index |
M-index |
Publishing since |
1 |
Molecular Genetics and Metabolism |
41 (9.09) |
1,226 |
23 |
34 |
1.045 |
2002 |
2 |
Journal of Inherited Metabolic Disease |
24 (5.32) |
1,397 |
21 |
24 |
0.808 |
1998 |
3 |
Clinical Chemistry |
18 (3.99) |
1,865 |
15 |
18 |
0.556 |
1997 |
4 |
Clinica Chimica Acta |
18 (3.99) |
619 |
14 |
18 |
0.609 |
2001 |
5 |
International Journal of Neonatal Screening |
14 (3.10) |
88 |
7 |
8 |
1.167 |
2018 |
6 |
Clinical Biochemistry |
13 (2.88) |
368 |
9 |
13 |
0.375 |
2000 |
7 |
Pediatrics |
13 (2.88) |
1,054 |
12 |
13 |
0.522 |
2001 |
8 |
Journal of Pediatric Endocrinology & Metabolism |
12 (2.66) |
89 |
6 |
9 |
0.545 |
2013 |
9 |
Rapid Communications in Mass Spectrometry |
11 (2.44) |
360 |
10 |
11 |
0.333 |
1994 |
10 |
Frontiers in Genetics |
9 (1.99) |
85 |
4 |
9 |
0.667 |
2018 |
11 |
Journal of Medical Screening |
8 (1.77) |
112 |
6 |
8 |
0.6 |
2014 |
12 |
Orphanet Journal of Rare Diseases |
8 (1.77) |
279 |
6 |
8 |
0.462 |
2011 |
13 |
Analytical Chemistry |
6 (1.33) |
194 |
6 |
6 |
0.4 |
2009 |
14 |
Genetics in Medicine |
6 (1.33) |
490 |
6 |
6 |
0.333 |
2006 |
15 |
Indian Journal of Pediatrics |
6 (1.33) |
78 |
5 |
6 |
0.385 |
2011 |
Table 4.
Most cited articles.
Table 4.
Most cited articles.
Rank |
Article Title |
Journal |
Year |
First Author |
Total Cita- tions
|
TC per Year |
Norma-lized TC |
Local Cita- tions |
LC/GC Ratio (%) |
1 |
Screening newborns for inborn errors of metabolism by tandem mass spectrometry |
New England Journal of Medicine |
2003 |
Wilcken, B |
483 |
23.0 |
4.66 |
130 |
5.48 |
2 |
Tandem mass spectrometric analysis for amino, organic, and fatty acid disorders in newborn dried blood spots: A two-year summary from the New England newborn screening program |
Clinical Chemistry
|
2001 |
Zytkovicz, TH |
394 |
17.13 |
3.56 |
83 |
21.07 |
3 |
Expanded newborn screening for inborn errors of metabolism by electrospray ionization-tandem mass spectrometry: Results, outcome, and implications |
Pediatrics
|
2003 |
Schulze, A |
355 |
16.90 |
3.42 |
117 |
32.96 |
4 |
Current status of newborn screening worldwide: 2015 |
Seminars in Perinatology |
2015 |
Therrell, BL |
329 |
36.56 |
8.30 |
36 |
10.94 |
5 |
Diagnosis of inborn-errors of metabolism from blood spots by acylcarnitines and amino-acids profiling using automated electrospray tandem mass spectrometry |
Pediatric Research
|
1995 |
Rashed, MS |
277 |
9.55 |
1.00 |
55 |
19.86 |
6 |
Clinical validation of cutoff target ranges in newborn screening of metabolic disorders by tandem mass spectrometry: A worldwide collaborative project |
Genetics in Medicine
|
2011 |
McHugh, DMS |
253 |
19.46 |
5.73 |
52 |
2.55 |
7 |
Effect of expanded newborn screening for biochemical genetic disorders on child outcomes and parental stress |
Jama - Journal of the American Medical Association |
2003 |
Waisbren, SE |
253 |
12.05 |
2.44 |
40 |
15.81 |
8 |
Rapid diagnosis of MCAD deficiency: quantitative analysis of octanoylcarnitine and other acylcarnitines in newborn blood spots by tandem mass pectrometry |
Clinical Chemistry
|
1997 |
Chace, DH |
233 |
8.63 |
1.01 |
43 |
18.45 |
9 |
Screening blood spots for inborn errors of metabolism by electrospray tandem mass spectrometry with a microplate batch process and a computer algorithm for automated flagging of abnormal profiles |
Clinical Chemistry
|
1997 |
Rashed, MS |
229 |
8.48 |
0.99 |
44 |
19.21 |
10 |
Neonatal screening for lysosomal storage disorders: feasibility and incidence from a nationwide study in Austria |
Lancet
|
2012 |
Mechtler, TP |
205 |
17.08 |
6.85 |
8 |
3.90 |
11 |
Natural history, outcome, and treatment efficacy in children and adults with glutaryl-CoA dehydrogenase deficiency |
Pediatric Research
|
2006 |
Koelker, S |
197 |
10.94 |
2.68 |
9 |
4.57 |
12 |
Electrospray tandem mass spectrometry for analysis of acylcarnitines in dried postmortem blood specimens collected at autopsy from infants with unexplained cause of death |
Clinical Chemistry
|
2001 |
Chace, DH |
192 |
8.32 |
1.74 |
46 |
23.96 |
13 |
The tandem mass spectrometry newborn screening experience in North Carolina: 1997-2005 |
Journal of Inherited Metabolic Disease |
2006 |
Frazier, DM |
154 |
8.56 |
2.10 |
61 |
39.61 |
14 |
Disorders of mitochondrial long-chain fatty acid oxidation and the carnitine shuttle |
Reviews in Endocrine & Metabolic Disorders |
2018 |
Knottnerus, SJG |
151 |
25.17 |
5.44 |
0 |
0 |
15 |
Untargeted metabolomic analysis for the clinical screening of inborn errors of metabolism |
Journal of Inherited Metabolic Disease |
2015 |
Miller, MJ |
148 |
16.44 |
3.73 |
8 |
5.41 |