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. Author manuscript; available in PMC: 2013 Oct 28.
Published in final edited form as: J Clin Epidemiol. 2011 Nov 1;65(1):10.1016/j.jclinepi.2011.07.006. doi: 10.1016/j.jclinepi.2011.07.006

Concordance of randomized and nonrandomized studies was unrelated to translational patterns of two nutrient-disease associations

Thomas A Trikalinos a,*, Denish Moorthy a, Mei Chung a, Winifred W Yu a, Jounghee Lee a, Alice H Lichtenstein a,b, Joseph Lau a
PMCID: PMC3809069  NIHMSID: NIHMS500749  PMID: 22047889

Abstract

Objective

There are several examples in nutrition of discordance between the results of observational studies and randomized controlled trials (RCTs). We hypothesized that this discordance is attributable to differences in the translational paths of nutrient–disease associations. Translational paths can be assessed using citation analysis.

Study Design and Setting

We compared the characteristics of citation networks using examples, where RCTs and observational studies agreed (long-chain n-3 polyunsaturated fatty acids [n-3 PUFA]) or disagreed (vitamin E). We performed systematic reviews in each example, constructed citation networks, and compared them with respect to the number of articles and citation relationships between them, as well as the distribution of articles’ hub and authority scores.

Results

For n-3 PUFA, meta-analyses of 14 RCTs and 10 observational studies both suggested that higher intake was associated with lower cardiovascular mortality. For vitamin E, the meta-analysis of 14 RCTs excluded a clinically significant effect, whereas 14 observational studies reported a significant inverse association. The respective citation networks consisted of 392 (n-3 PUFA) and 351 (vitamin E) articles. No differences between the characteristics of the two networks were identified. There was no evidence that the observational studies predated RCTs in the translational process in either example.

Conclusion

In the two examples, citation network characteristics do not predict concordance in the results of observational studies and RCTs.

Keywords: Citation analysis, Network analysis, Translational research, Nutritional associations, Vitamin E, Omega-3 fatty acids

1. Context

Observational data have suggested a strong association between a number of dietary factors and chronic disease risk [1-5]. However, randomized controlled trials (RCTs) designed to assess the efficacy of these dietary factors with respect to health outcomes have yielded, for the most part, negative results (fiber and colon cancer [6], vitamin E and cardiovascular disease [7], vitamin E and lung cancer [8], β-carotene and cancer [8], β-carotene and coronary events [9], vitamin C and cardiovascular disease [10], and folate and cardiovascular disease [11]).

The outcomes of these trials were both disappointing to the healthcare community and confusing to the general public. The trials were expensive to conduct, and in some cases, identified adverse effects of nutrient supplementation [8]. The discrepancies raised serious questions about the currently used approach for determining whether the evidence base is adequate to justify launching a large-scale RCT with hard endpoints as the outcome measure.

Deciding which specific nutrient–disease association to further evaluate in human intervention trials is challenging. Apart from the expected impact of a nutritional intervention on public health, and the feasibility and logistics of conducting a trial, additional critical components need to be factored into the decision. These pertain to the maturity and reliability of the relevant evidence base (that is, the strength of the data supporting a potential nutrient–disease association), the biological plausibility of the association, the reliability of existing data, and the likelihood of bias and systematic errors affecting the interpretation of the available data. The evidence base is formed by the interplay of various translational paths, in which an initial hypothesis-forming observation supports subsequent research and is eventually “translated” to interventions for preventing or treating human disease. It is possible that nutrient associations where RCT and observational data are concordant have a more extensive and mature evidence base, compared with associations where the data are discordant. Therefore, further understanding of the translational paths that shape the evidence base in each topic is of interest. Fig. 1 describes alternative scenarios for the possible cascade of translational events. The simplistic model in Fig. 1a purports a linear progression from an initial experiment in the laboratory to a succession of research studies that eventually lead to observational studies and then to RCTs in humans. If anything, anecdotal observations suggest a much more circuitous path, such as that in Fig. 1b, in which there is no clear succession of study types. To some extent, such patterns of information flow can be assessed with citation analysis, which is a qualitative and quantitative representation of citation relationships among publications.

Fig. 1.

Fig. 1

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Simplistic (a) and more complex (b) hypothetical translational paths connecting a seminal observation to eventual randomized controlled trials (RCTs) in humans t: time. Each node represents a study/publication that “informs” subsequent publications—“information” relationships are shown as arcs. (Citation relationships can be considered as a proxy of these information relationships). In the simplistic linear translation model on the left panel (a), a hypothetical first (seminal) observation starts from an in vitro study in the lab (lowest left white node), and eventually gets translated to RCT in humans through a succession of research in animal disease models and epidemiological studies in humans. Each design builds on the findings of the previous one, and there is a temporal succession: in particular, RCTs are performed after the observational studies, as they are motivated, designed, and launched based on observational data. We are not aware of any empirical evidence that the linear scenario of panel a is actually observed for nutrient–disease relationships. If anything, anecdotal observations suggest a much more circuitous path, such as that in panel b: the first observation about a nutrient–disease association is made in humans. This spurs a complex network of interrelated research activity. Related hypotheses are tested in subsequent explorations using observational data, studies in animal models, and in RCTs. For example, the observation that long-chain n-3 polyunsaturated fatty acids (n-3 PUFA) may be associated with beneficial cardiovascular disease outcomes was first made in humans, and not in the lab: Greenland Eskimos consume a diet rich in n-3 PUFA and have a low incidence of cardiovascular disease compared with genetically related Danes [109,110]. This seminal observation has spurred a large body of research of various types.

We hypothesize that differences in the observed flow of information (as captured by citations that are received or made among publications) through the various translational paths and the content of the propagated information are associated with concordance or discordance in the results of observational studies and RCTs. For example, a limited evidence base and information flow may indicate inconsistency of study results and thus may be associated with topics where RCTs and observational studies disagree. Reciprocally, a large evidence base with higher information flow may indicate consistency of findings and general agreement between RCTs and observational studies. Of course, these are not one-to-one relationships; it is conceivable that profound inconsistencies and disagreements between studies could lead to considerable discourse among investigators, which in turn would increase information flow. We set out to empirically explore our hypothesis by analyzing and comparing characteristics of the citation networks in two nutritional associations with disease: one where the two research designs generally agree, and one where they disagree.

2. Materials and methods

2.1. Selection of the concordant and the discordant example

For proof of concept, we decided to study the evidence base for two nutrient associations of disease outcomes. After feedback from a technical expert panel composing of four nutritional epidemiology and methodology experts, we selected two nutritional associations with cardiovascular mortality: one where the results of RCTs and prospective cohorts (“observational studies”) were statistically significant and had the same direction (“concordant” example); and one where the summary of observational studies showed a statistically significant effect, but that of the RCTs excluded any clinically important effect (“discordant” example). We chose a hard clinical outcome because such outcomes have high potential impact on public health and strongly influence clinical practice guidelines.

For the “concordant” example, we selected the relationship between the very long-chain n-3 polyunsaturated fatty acids (n-3 PUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and cardiovascular mortality. Based on systematic reviews and meta-analyses from our team [12,13] and others [14,15], both observational studies and RCTs associated higher EPA and DHA intake with lower cardiovascular mortality. For the “discordant” example, we selected the relationship between vitamin E intake and cardiovascular disease mortality. A meta-analysis of observational studies suggested a statistically significant association with decreased risk of coronary heart disease [16], whereas a meta-analysis of large RCTs excluded any clinically important effect [17].

For each topic, we performed de novo systematic reviews and meta-analyses of RCTs and observational studies to become familiar with the literature and verify characterizations of “concordance” or “discordance.” We searched PubMed to identify eligible reports of RCTs and observational studies, screened them for eligibility according to predefined criteria, extracted data, and performed meta-analyses. Details of the systematic review methodology, the characteristics of the eligible studies, and the results of the quantitative synthesis are provided in the online Appendix on the journal’s Web site at www.jclinepi.com.

2.2. Identifying the evidence base in the two examples

The search strategies included keywords related to the nutrients of interest (n-3 PUFA or vitamin E), cardiovascular disease, and study design terms related to observational studies or RCTs (see online Appendix for the search strategies on the journal’s Web site at www.jclinepi.com). Searches were conducted during June and July of 2010 and were limited to English-language publications. We considered that the set of publications identified in PubMed contain an adequate representation of the corresponding clinical evidence base. We also assumed that this evidence base would include influential articles along major translational paths.

2.3. Construction of citation networks

We then constructed the citation networks of the RCTs and observational studies included in our systematic reviews (“index” articles), and represented them as citation graphs. The online Appendix (on the journal’s Web site at www.jclinepi.com) provides details for how we formed the citation graphs and how we verified that they possess and fulfill theoretically anticipated properties and constraints. Briefly, among the set of articles returned by the PubMed searches, we identified those cited by the index studies directly or following citation links through one or more intermediary papers using the Thompson ISI database.

A citation graph describes citation relationships between articles in the evidence base (Fig. 2). Articles are represented by vertices and citation relationships by arcs that connect pairs of vertices. The direction of each arc is from the cited toward the citing article (following the flow of information). Representing citation relationships as graphs allows us to use tools from graph theory and network analysis [18-21] to characterize the evidence base and the apparent information flow. Without loss of clarity, we use the terms “citation network” and “citation graph” interchangeably.

Fig. 2.

Fig. 2

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Example of a citation network of six articles. The figure shows a citation network (represented as a citation graph) in a hypothetical evidence base of six articles. Each article is depicted by a vertex (A through F). The horizontal placement of the articles corresponds to their year of publication; their vertical arrangement is arbitrary–its main purpose is clarity of presentation. Arcs denote citation relationships. The direction of the arc indicates flow of information from the cited paper (beginning of the arc) to the citing paper (end of the arc). Five out of six papers (papers B through F) are connected with citation arcs. There are four observed citation arcs (B → D, C → D, C → E, and D → F) out of a total of 15 possible ones (from any earlier- to any subsequently published article). The density of the citation relationships is defined as the ratio of observed to possible citation arcs, that is, here it is 4/15 = 0.27. Citation graphs have characteristics and properties that are described in the Appendix on the journal’s Website at www.elsevier.com. Briefly, citation arcs are simple directed acyclic graphs: (1) An article does not cite itself, and there is at most one citation relationship between two articles (simple graph); (2) if one follows the direction of the citation arcs along any possible path, one cannot visit the same article twice, that is, there are no circular directed paths (directed acyclic graph). (3) In addition, there is a temporal consistency constraint, for example, an earlier-published article cannot cite a later-published article.

2.4. Size and connectivity of citation networks

The citation networks generated are treated as operational representations of the clinical evidence base for n-3 PUFA and vitamin E. A limited evidence base (in terms of number of articles or number of citation connections between them) may indicate inconsistencies in the findings of several studies, and thus may be encountered in topics where RCTs and observational studies disagree. Reciprocally, fields where there is general congruence in the study findings may have many articles and numerous citation connections.

2.4.1. Articles in the citation network that report primary data in humans (pertinent articles)

In the past, we have encountered topics where there are more reviews and commentaries than papers with primary data [22-25]. It is therefore important to limit the analysis of citation relationships to the subset of articles that report primary data in humans. To this end, we reviewed the abstracts of the articles in the citation networks and recorded whether the article included primary data in humans (yes, no). We also recorded whether there was a clear statement describing the “intervention” or “exposure” as the nutrient of interest, and whether any clinical cardiovascular outcomes were reported. Articles containing primary data in humans and describing the exposure and the outcomes of interest were deemed pertinent to the association. Examples of nonpertinent articles are methodology articles, and those referring to different nutrients (e.g., alpha-linolenic acid instead of EPA or DHA for n-3 PUFA or antioxidants in general rather than vitamin E), or endpoints other than clinical cardiovascular outcomes (e.g., depression, diabetes, hypertension, lipid profiles).

2.4.2. Quantification of citation network size and connectivity

Both for the initial citation networks and those limited to pertinent studies, we counted the total number of articles and the total number of citation relationships between articles in the network. These were only a subset of the total counts of citations received by an article. For example, the study on vitamin E and coronary heart disease in men by Rimm et al. [26], received 101 citations within the network but has received over 1,582 citations in total. We also recorded the number of citations made and number of citations received by each article (calculating the density of the citation relationships as per Fig. 2), and the articles’ hub and authority scores. These quantify an article’s importance in the citation network. The hub score is higher for articles that cite a lot of other articles (“integrate more information”), which are in turn connected to other articles that make many citations. The authority score is higher for articles that receive a lot of citations and are also connected to other articles that receive a lot of citations. These metrics convey information on the connectivity of the graph and the relative importance of articles in a network. We compared them across the n-3 PUFA and vitamin E examples using quantile–quantile (QQ) plots and Mann–Whitney tests. We used chi-square tests for discrete characteristics.

2.4.3. Relative timing between RCTs and observational studies

We collected the enrollment periods of the RCTs included in the systematic reviews and examined whether they preceded the year of publication of the observational studies. It is likely that most RCTs are conceived and designed at least a year before randomizing the first patient. Therefore, the start of the enrollment period is a conservative proxy of the time when the RCT was conceived. When enrollment periods were not reported, we examined other publications of the same RCT (if available). If no data were found, we imputed the start of the enrollment period as (year of publication—follow-up duration—1 year) and its end as (year of publication—1 year).

2.4.4. Characterizing information flow in the main path of the citation networks

Main path articles integrate maximal information from previous articles and propagate information to other articles [18,19,27,28]. They represent the most important stream of propagation of information in a citation network [18,19,29]. By representing “major” citation relationships between key articles, the main path can provide an abstraction of the type of information that flows in a citation network. We calculated the main path of each citation network using an iterative algorithm [27,28], and reviewed the full text of its articles. Examples of articles that are likely to be selected in the main path are major RCTs or major observational studies (including seminal articles) because they are often cited as key articles; and systematic reviews and meta-analyses, because they make references to relevant articles, and because they are often cited by subsequently published articles as state-of-the-science summaries.

3. Results

3.1. Meta-analyses of RCTs and observational studies

We performed separate meta-analyses of RCTs and observational studies (prospective cohorts) for the n-3 PUFA and vitamin E examples. The online Appendix (on the journal’s Web site at www.jclinepi.com) describes the characteristics of the eligible studies for each systematic review, and the results of the quantitative analyses for cardiovascular mortality outcomes.

Briefly, in the n-3 PUFA example, we identified 14 RCTs (reported in 15 publications) [30-44] and 10 prospective cohorts [45-54] (see Tables 1 and 2 in the online Appendix on the journal’s Web site at www.jclinepi.com). Summary results from meta-analyses of RCTs and observational studies were statistically significant and suggested lower risk of cardiovascular mortality with higher n-3 PUFA intake or supplementation. In RCTs, the random-effects meta-analysis relative risk was 0.88 (95% confidence interval [CI]: 0.82, 0.95—in 10 out of 14 trials with analyzable data [45-54], that is, 10 of the 14 trials of the systematic review that contributed to the meta-analysis). In 6 out of 10 prospective cohorts with analyzable data on cardiovascular mortality [45,46,49-51,54], mixed-effects meta-regressions suggested a dose–response association between higher EPA and DHA intakes up to 0.20 g per day and decreased risk of cardiovascular mortality (OR = 0.62, 95% CI: 0.45, 0.86 per 0.20 g of daily intake), with no statistically significant change in risk for higher average intakes.

In the vitamin E example, we identified 14 RCTs [9,10,55-66] and 14 prospective cohorts [26,67-79] (see Tables 3 and 4 in the online Appendix on the journal’s Web site at www.jclinepi.com). The summary relative risk of the 14 RCTs was statistically nonsignificant and excluded any clinically important effect (relative risk = 0.97, 95% CI: 0.91, 1.03), with no evidence of heterogeneity. In contrast, a random-effects meta-analysis of eight observational studies with analyzable data [67-74] suggested an association between higher daily vitamin E intake and lower risk of cardiovascular mortality (summary hazard ratio 0.85, 95% CI: 0.78, 0.93), with little evidence of heterogeneity (I2 = 26%, P-value = 0.13).

3.2. Size and connectivity of citation networks

Our searches returned 2,741 and 2,825 articles for n-3 PUFA and vitamin E, respectively. Both citation networks were sparsely connected; citation graph densities (ratio of observed to possible citation relationships) were in the order of 10−3. As shown in Table 1, although the two citation networks had similar number of articles, the n-3 PUFA network had more citation relationships (n = 2,193) than the vitamin E network (n = 1,519).

Table 1.

Characteristics of citation networks in the two examples

Citation network or subset Number of articles
Number of citation relationships
n-3 PUFA (n = 2,741) Vitamin E (n = 2,825) n-3 PUFA Vitamin E
Network of all articles “sending” information to the “index” publications 392a 351b 2,193 1,519
Subset of “pertinent” articlesc 71a 69b 276 281
Subset of index articles only 25 28 37 87
Articles in the main path 21 18 22 22
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Abbreviations: n-3 PUFA, long-chain n-3 polyunsaturated fatty acids.

a

These include the reports of the index randomized trials (n = 15) and observational studies (n = 10).

b

These are the index randomized trials (n = 14) and observational studies (n = 14).

c

Pertinent to the association between the respective nutrient and clinical cardiovascular outcomes as deemed on full-text review.

3.2.1. Connected subsets of the citation networks

For n-3 PUFA, 392 (out of 2,741) articles were connected to at least one index publication via a citation relationship vs. 351 (out of 2,825) articles for vitamin E (P = 0.04, by chi-square test; Table 1, Fig. 3).

Fig. 3.

Fig. 3

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Citation networks including all studies sending information to an index article (i.e., an article included in our systematic reviews) the long-chain n-3 polyunsaturated fatty acids (panel a) and vitamin E (panel b) examples. Red-colored vertices denote index publications of RCTs. Blue-colored vertices denote index observational studies. Empty vertices without color are articles with primary data in humans that are pertinent to the association between the nutrient and clinical cardiovascular outcomes. Small black-filled vertices denote publications that have no primary data in humans (e.g., systematic or narrative reviews, studies in animals, commentaries) or that have primary data but are not pertinent to the association of interest (e.g., report on changes in lipid profiles or blood pressure rather than clinical cardiovascular outcomes). The horizontal positioning is the year of publication. The vertical positioning is arbitrary (chosen to enhance clarity of presentation).

The QQ plots in Fig. 4 compare distributions of the number of citations received (panel a) or made (panel b) by each article from other publications. The plots suggest that these numbers were larger for n-3 PUFA than vitamin E (Mann–Whitney test P < 0.001 and P = 0.013 for panels 4a and 4b, respectively).

Fig. 4.

Fig. 4

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Quantile–quantile (QQ) plots for the number of citations made to other papers (left panel) or received from other papers (right panel). The axes indicate number of citations. QQ plots are used to compare two distributions (one in the long-chain n-3 polyunsaturated fatty acids [n-3 PUFA] example and one in the vitamin E example) by plotting corresponding quantiles against each other. If the distributions were indistinguishable, the respective quantiles would be equal and all the points would line on the diagonal. The majority of points are above the diagonal in both panels, suggesting higher counts of citations made or citations received for n-3 PUFA rather than the vitamin E. The Mann–Whitney test was significant (P < 0.001 in the left panel, and P = 0.013 in the right panel). Hub score distributions were also statistically significantly different between the two topics (P < 0.001), but authority score distributions did not differ beyond chance (P = 0.16).

In both topics, the top three most cited articles were published in general medical journals with high impact factors (Journal of the American Medical Association, The Lancet, and the New England Journal of Medicine). The three most cited articles in the n-3 PUFA citation network were an observational study in the Netherlands (Zutphen study) that associated higher fish intake with lower cardiovascular mortality (108 citations received) [80]; a prospective nested case–control study that found a strong association between serum levels of n-3 PUFA and lower risk of sudden death in patients with history of heart disease (an index study that received 71 citations) [54]; and an observational study (Chicago Western Electric Study) reporting an association between higher fish intake and lower risk of sudden and other cardiovascular death (55 citations received) [81].

All three most cited papers in the vitamin E example were index articles: a report from the Health Professionals Follow-up Study suggesting a negative association between the use of vitamin E supplements and coronary heart disease in men (101 citations received) [26]; an analysis from the Nurses’ Health Study prospective cohort suggesting that among middle-aged women, the use of vitamin E supplements was associated with a reduced risk of coronary heart disease (85 citations received) [79]; and the Cambridge Heart Anti-oxidant Study RCT that found a beneficial effect of vitamin E supplementation on the rate on nonfatal myocardial infarctions, but not on cardiac mortality (CHAOS trial, 70 citations received) [56].

3.2.2. Articles that reported primary data in humans and were pertinent to the association

As shown in Fig. 5, citation networks limited to the subset of pertinent articles were comparable across the two examples. For n-3 PUFA, 71 out of the 392 articles (18%) had primary data in humans and were pertinent to the association of EPA or DHA with clinical cardiovascular outcomes. The corresponding number for vitamin E was 69 out of 351 articles (20%; P = 0.64 by chi-square test for the comparison between the two topics).

Fig. 5.

Fig. 5

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Citation networks of the subset of studies that have primary data in humans and are pertinent to the associations examined. Panel a: long chain n-3 polyunsaturated fatty acids. Panel b: Vitamin E. Red-colored vertices denote index publications of RCT (i.e., those included in our systematic reviews). Blue-colored vertices denote index observational studies (i.e., those included in our systematic reviews). The remaining vertices are articles with primary data in humans that are pertinent to the association between the nutrient and clinical cardiovascular outcomes. Of these, RCTs are colored in pink. This figure was generated from the citation networks of Fig. 3 after excluding the small black vertices.

3.2.3. Relative timing between RCTs and observational studies

For both n-3 PUFA and vitamin E, the enrollment periods of at least two RCTs started before or in the same year as the earliest-published observational study in our systematic review (Fig. 6). For n-3 PUFA, only one [37] of the three largest RCTs (corresponding to four publications in the systematic review) [32,33,37,41] started enrolling participants after several (three) observational studies were published. In vitamin E, no index observational study was published before the start of the enrollment period of two [55,61] of the three largest RCTs [10,55,61].

Fig. 6.

Fig. 6

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Enrollment periods of randomized controlled trials (RCTs) and years of publication of index RCTs and observational studies (i.e., those included in our systematic reviews). Panel a: long-chain n-3 polyunsaturated fatty acids. Panel b: Vitamin E. Red-colored vertices denote index publications of RCTs. Blue-colored vertices denote index observational studies. Vertices have area proportional to the size of the each (normalized within each study type). The red horizontal bars on top denote the enrollment periods of RCTs, reported (solid) or imputed (dashed).

3.2.4. Information flow in the main path

We were not able to identify qualitative differences in the main path articles in the two examples. Main path articles in the n-3 PUFA example pertained to the relationship of fish oil or EPA/DHA with cardiovascular risk factors such as lipid profiles, blood pressure/hypertension, hemostasis, intermediate outcomes such as arrhythmia, and hard cardiovascular outcomes including myocardial infarction, stroke, and cardiovascular mortality (Table 2). They included several large prospective cohorts and RCTs, and three systematic reviews or meta-analyses. The articles on the main path of the vitamin E example included seven RCTs and six observational studies on the relationship between vitamin E or other antioxidants with cardiovascular morbidity and cardiovascular or all-cause mortality, and three systematic reviews with meta-analyses (Table 3).

Table 2.

Main path articles in the n-3 PUFA example

Study Title Journal Design References madea Citations receiveda
van Gent, 1979 [83] Effect, on serum lipid levels of omega-3 fatty acids, of ingesting fish-oil concentrate Lancet RCT 0 1
Mortensen, 1983 [84] The effect of N-6 and N-3 polyunsaturated fatty acids on hemostasis, blood lipids, and blood pressure Thromb Haemost RCT 1 23
Norris, 1986 [85] Effect of dietary supplementation with fish oil on systolic blood pressure in mild essential hypertension BMJ RCT 1 17
Knapp, 1989 [86] The antihypertensive effects of fish oil. A controlled study of polyunsaturated fatty acid supplements in essential hypertension NEJM RCT 2 37
Simopoulos, 1991 [87] Omega-3 fatty acids in health and disease and in growth and development AJCN Review 8 16
Guallar, 1995 [88] A prospective study of plasma fish-oil levels and incidence of myocardial infarction in US male physicians JACC OBS 5 19
Ascherio, 1995 [89] Dietary intake of marine n-3 fatty acids, fish intake, and the risk of coronary disease among men NEJM OBS 3 55
Daviglus, 1997 [81] Fish consumption and the 30-year risk of fatal myocardial infarction NEJM OBS 5 55
Albert, 1998 [54] Fish consumption and risk of sudden cardiac death JAMA OBS 6 71
deLorgeril, 1999 [90] Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study Circulation RCT 5 34
Hu, 2002 [91] Fish and omega-3 fatty acid intake and risk of coronary heart disease in women JAMA OBS 11 36
Mozaffarian, 2003 [92] Cardiac benefits of fish consumption may depend on the type of fish meal consumed: the Cardiovascular Health Study Circulation OBS 5 19
Mozaffarian, 2004 [93] Fish intake and risk of incident atrial fibrillation Circulation OBS 5 10
Calò, 2005 [31] N-3 Fatty acids for the prevention of atrial fibrillation after coronary artery bypass surgery: a randomized, controlled trial JACC RCT 7 7
Wang, 2006 [13] n-3 Fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review AJCN SR/MA 48 3
Breslow, 2006 [94] n-3 fatty acids and cardiovascular disease AJCN Review 38 1
Mozaffarian, 2006 [95] Fish intake, contaminants, and human health: evaluating the risks and the benefits JAMA SR/MA 49 4
Kaushik, 2008 [48] Frequency of fish consumption, retinal microvascular signs, and vascular mortality Micro-circulation OBS 7 0
Jenkins, 2008 [96] Fish-oil supplementation in patients with implantable cardioverter defibrillators: a meta-analysis CMAJ SR/MA 24 1
Mozaffarian, 2008 [97] Dietary fish and omega-3 fatty acid consumption and heart rate variability in US adults Circulation OBS 12 1
Tavazzi, 2008 [37] Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomized, double-blind, placebo-controlled trial Lancet RCT 16 0
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Abbreviations: n-3 PUFA, long-chain n-3 polyunsaturated fatty acids; AJCN, American Journal of Clinical Nutrition; BMJ, British Medical Journal; JAMA, Journal of the American Medical Association; JNCI, Journal of the national Cancer Institute; OBS, observational study; RCT, randomized controlled trial; SR/MA, systematic review/meta-analysis.

a

The counts in the last two columns refer to references made to other articles in the corpus and citations received from other articles in the corpus, respectively.

Table 3.

Main path articles in the vitamin E example

Study Title Journal Design References madea Citations receiveda
Stahelin, 1984 [98] Cancer, vitamins, and plasma lipids: prospective Basel study JNCI OBS 0 5
Gey, 1987 [99] Plasma levels of antioxidant vitamins in relation to ischemic heart disease and cancer AJCN Review 1 24
Rimm, 1993 [26] Vitamin E consumption and the risk of coronary heart disease in men NEJM OBS 3 101
Hodis, 1995 [100] Serial coronary angiographic evidence that antioxidant vitamin intake reduces progression of coronary artery atherosclerosis JAMA OBS 3 21
Stephens, 1996 [56] Randomized controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS) Lancet RCT 4 70
Ogunyankin, 1996 [101] Vitamin E and coronary heart disease Lancet Letter 1 1
Rapola, 1997 [9] Randomized trial of alpha-tocopherol and beta-carotene supplements on incidence of major coronary events in men with previous myocardial infarction Lancet RCT 7 22
Leppala, 2000 [102] Controlled trial of alpha-tocopherol and beta-carotene supplements on stroke incidence and mortality in male smokers Arterio-scler Thromb Vasc Biol RCT 6 8
Boaz, 2000 [57] Secondary prevention with antioxidants of cardiovascular disease in end-stage renal disease: randomized placebo-controlled trial Lancet RCT 4 15
Muntwyler, 2002 [103] Vitamin supplement use in a low-risk population of US male physicians and subsequent cardiovascular mortality Arch Intern Med OBS 11 4
Satia-About, 2003 [104] Dietary supplement use and medical conditions: the VITAL study Am J Prev Med OBS 5 1
Miller, 2005 [105] Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality Ann Intern Med SR/MA 11 17
Lee, 2005 [61] Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women’s Health Study: a randomized controlled trial JAMA RCT 19 7
Bardia, 2008 [106] Efficacy of antioxidant supplementation in reducing primary cancer incidence and mortality: systematic review and meta-analysis Mayo Clin Proc SR/MA 13 2
Bjelakovic, 2008 [107] Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases Cochrane Database Syst Rev SR/MA 92 2
Sesso, 2008 [10] Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians’ Health Study II randomized controlled trial JAMA RCT 23 1
Lin, 2009 [108] Vitamins C and E and beta-carotene supplementation and cancer risk: a randomized controlled trial JNCI RCT 7 1
Pocobelli, 2009 [72] Use of supplements of multivitamins, vitamin C, and vitamin E in relation to mortality Am J Epidemiol OBS 15 0
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Abbreviations: AJCN, American Journal of Clinical Nutrition; JAMA, Journal of the American Medical Association; JNCI, Journal of the national Cancer Institute; Lab, laboratory study; OBS, observational study; RCT, randomized controlled trial; SR/MA, systematic review/meta-analysis.

a

The counts in the last two columns refer to references made to other articles in the corpus and citations received from other articles in the corpus, respectively.

4. Discussion

We analyzed the citation networks of publications on the associations of n-3 PUFA and vitamin E with cardiovascular mortality. We observed that, in both examples, citation networks were grossly similar with respect to their quantitative characteristics (such as the number of articles and citation relationships among articles), and the connectivity of the articles. This was also true for citation networks limited to the subset of articles that described primary data in humans and were pertinent to the association between the nutrients and clinical cardiovascular outcomes. In both examples, there was no indication that the research that led to the index RCTs and observational studies proceeded in a sequential fashion, with observational studies preceding RCTs. For both examples, at least two RCTs enrolled their first patient before or on the same calendar year that the earliest-published index observational study appeared in the literature.

Research builds on previous findings. Biomedical knowledge advances as scientific data and its interpretation are communicated toward informing further research. Scientific publications are the generally accepted vehicle for such communications, and the citation networks they form are a representation of the flow of biomedical knowledge through various translational paths [27]. From this point of view, analysis of citation networks may provide insights on the size and maturity of the relevant evidence base. Further in some extreme cases, it may demonstrate the propagation of erroneous conclusions, and help understand the formation and establishment of unfounded belief systems in the medical community [82].

We hypothesized that nutrient associations of disease where RCTs and observational studies agree in the direction and significance of their findings may differ in the size of their evidence base, and the patterns of information flow in it. Although we found small differences in the quantitative characteristics of the citation networks of the n-3 PUFA and the vitamin E examples, these were not dramatic. Thus, there is no suggestion that quantitative analyses of citation relationships can distinguish topics where RCTs and observational studies agree or disagree. Our negative finding is easy to explain. Only the most dramatic aberrations in a translational path would have been identified in an analysis of citation relationships. An example would be a whole body of literature generated from an unwarranted extrapolation of previous findings. There is no evidence that any such aberrations occurred in the two examples we explored.

Notwithstanding the aforementioned observations, this article introduced methodologies for the quantitative analysis of citation networks as proxies for understanding translational paths. In analyzing the two examples, we found no empirical support of the notion that research translation progresses in a linear fashion, at least in the rightmost end of the translational spectrum, where hypotheses are being evaluated in humans. If anything, the index RCTs and observational studies (the reports that represent the state of knowledge in the two examples) were published over the same time period. If anything, Fig. 6 questions whether the design and launching of most index RCTs could had been informed by the majority of index observational studies.

There are limitations to using citation analysis to understand translational paths in a given topic. Citing previous research is a complex process. As much as we would like citation practices to be impartial and scientific, they are influenced by personal beliefs, biases, and preferences, and are subject to citation distortion. The latter includes citation bias, that is, when one systematically ignores articles that contain content at odds with ones claims; citation amplification where a lot of citations propagate a belief without any evidence support; and citation invention, that includes citing content but ascribing different meaning to it and converting an hypothesis to fact through citation alone [82]. Our searches may have missed early publications that potentially influenced subsequent work, either observational or experimental, and most of the publications in the citation network (with the exception of those included in the systematic reviews) were not assessed in detail for content, pertinence to the association, or methodological quality. The two examples chosen both had cardiovascular mortality as an outcome and results might have been different for non-mortality outcomes. Publication bias, which occurs as a result of researchers publishing only studies with significant positive results and ignoring studies that report nonsignificant results, also affects the citation network. Lastly, much of the work cited for the two examples was published before a registry of clinical trial was established (www.clinicaltrials.gov). Hence, we cannot rule out the possibility that reporting bias confounded our conclusions.

Despite the above limitations, we believe that citation analysis is one of the few representations of the translational process that can be objectively quantified. It merits attention as it can provide a framework to analyze the series of research steps that led to RCTs in humans, and perhaps identify unwarranted extrapolations in the translational process, if any exist [82]. We believe that an empirical exploration of citation relationships for a larger number of nutrient/disease associations is necessary to adjudicate our conclusion that most index RCTs could not had been informed by the mass of corresponding observational studies in either example examined in the present study.

Supplementary Material

Supplementary Appendix

What is new?

  • For many nutrient associations of disease, randomized controlled trials (RCTs) and observational studies reach conflicting results. Explanations for such discordances may be traceable in the translational paths leading to RCTs and observational studies—but this has not been studied till now.

  • We analyzed the citation networks of publications on the associations of long-chain n-3 polyunsaturated fatty acids (n-3 PUFA) and vitamin E with cardiovascular mortality.

  • We observed that the citation networks in both examples are grossly similar with respect to quantitative characteristics of the networks, such as the number of articles and citation relationships among articles, and the connectivity of the articles.

  • Analyses of the translational paths suggest that most RCTs could not have been informed by the mass of corresponding observational studies for either nutrient example, implying that translation of research in the area of nutrient supplementation and cardiovascular outcomes does not follow a linear succession of research designs.

Acknowledgments

Funding: This article is based on work performed with funding from the Office for Dietary Supplements commissioned through the Agency for Healthcare Research and Quality (Contract number HHSA 290 2007 100551, task order 5). None other than the authors had any role in study design, collection, analysis, or interpretation of data, in the writing of the report, or the decision to submit the paper for publication. The authors are independent from the funders.

Footnotes

Contributors: T.A.T. and J.Lau had the initial idea. T.A.T. designed the study and drafted the protocol with input from J.Lau. T.A.T., D.M., W.W.Y., J.Lee, and M.C. acquired the data. T.A.T. developed software for citation graph manipulation and analyses and wrote the first draft of the paper. All authors critically revised the paper. No other person including medical editors has assisted in any way in the writing or the preparation of the article. T.A.T. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Supplementary data

Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.jclinepi.2011.07.006.

Competing interests: We declare that none of the authors has a conflict of interest in this submission. All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare that no author has support from companies for the submitted work. No other relationships or activities that could appear to have influenced the submitted work.

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