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Trikalinos TA, Moorthy D, Chung M, et al. Comparison of Translational Patterns in Two Nutrient-Disease Associations: Nutritional Research Series, Vol. 5. Rockville (MD): Agency for Healthcare Research and Quality (US); 2011 Oct. (Technical Reviews, No. 17.5.)

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Comparison of Translational Patterns in Two Nutrient-Disease Associations: Nutritional Research Series, Vol. 5.

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Results

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. Appendix A describes the characteristics of the eligible studies for each systematic review, as well as 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 cohorts45–54 (Appendix Tables A1 and A2). 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 of 14 trials with analyzable data 45–54, i.e., 10 of the 14 trials of the systematic review that contributed to the meta-analysis). In 6 of 10 prospective cohorts with analyzable data on cardiovascular mortality45, 46, 49–51, 54, mixed effects meta-regressions suggested a dose-response association between higher EPA and DHA intakes up to 0.20 grams per day and decreased risk of cardiovascular mortality (Odds ratio = 0.62, 95% CI 0.45, 0.86 per 0.20 grams of daily intake), with no statistically significant change in risk for higher average intakes.

In the vitamin E example, we identified 14 RCTs9, 10, 55–66 and 14 prospective cohorts26, 67–79 (Appendix Tables A3 and A4). 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 data67–74 suggested an association between higher daily vitamin E intake and lower risk of cardiovascular mortality (summary hazard ratio 0.85, 95% CI: 0.78 to 0.93, with little evidence of heterogeneity (I2 = 26%, p-value = 0.13).

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) that the vitamin E network (n=1,519).

Table 1. Characteristics of citation networks in the two examples.

Table 1

Characteristics of citation networks in the two examples.

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, versus 351 (out of 2,825) articles for vitamin E (P=0.04, by chi-square test; Table 1, Figure 3).

Panel a: n-3 PUFA example. Panel b: Vitamin E example. 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). All other vertices denote articles that “send” information to an index study, either directly or through intermediaries. Of these, 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 filled black 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). Both examples look very similar. There are 392 articles and 2193 arcs between them in the n-3 PUFA example and 351 articles and 1519 arcs between them in the vitamin E example.

Figure 3

Citation networks including all studies sending information to an index article. Panel a: n-3 PUFA. Panel b: Vitamin E. Red-colored vertices denote index publications of RCTs (i.e., those included in our systematic reviews). Blue-colored vertices denote (more...)

The quantile–quantile plots in Figure 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).

Quantile-quantile plots are used to compare two distributions (one in the n-3 PUFA example and one in the vitamin E example) by plotting corresponding quantiles against each other. The figure compares the distributions of the number of citations received (left) or made (right) by each article in the two examples. If the distributions were the same the respective quantiles would be equal and all the points would line on the diagonal. It appears that the majority of points are above the diagonal in both panels, suggesting that the distribution of the citations received and made in the n-3 PUFA example is shifted towards higher counts.

Figure 4

Quantile-quantile plots of the distributions of citations to and from other papers in the connected subset. The axes indicate number of citations. Quantile–quantile plots are used to compare two distributions (one in the n-3 PUFA example and one (more...)

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 a 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 is associated with a reduced risk of coronary heart disease (85 citations received)79; and the Cambridge Heart Antioxidant Study RCT, which 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.

Articles That Reported Primary Data in Humans and Were Pertinent to the Association

As shown in Figure 5, the citation networks limited to the subset of pertinent articles are comparable across the two examples. For n-3 PUFA, 71 out of the 392 articles (18 percent) of the connected subset 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 percent; P=0.64 by chi-square test for the comparison between the two topics).

Panel a: n-3 PUFA example. Panel b: Vitamin E example. 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, RCT are colored in pink. The horizontal positioning is the year of publication. The vertical positioning is arbitrary (chosen to enhance clarity of presentation). This figure is generated from the citation networks of Figure 3 after excluding the small black vertices. Both examples look very similar. There are 71 articles and 276 arcs between them in the n-3 PUFA example and 69 articles and 281 arcs between them in the vitamin E example.

Figure 5

Citation networks of the subset of studies that have primary data in humans and are pertinent to the associations examined. Panel a: n-3 PUFA. Panel b: Vitamin E. Red-colored vertices denote index publications of RCTs (i.e., those included in our systematic (more...)

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 (Figure 6). For n-3 PUFA, only one37 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 two55, 61 of the three largest RCTs10, 55, 61.

Panel a: n-3 PUFA example. Panel b: Vitamin E example. 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). Vertices have area proportional to the size of the each (normalized within each study type). The red horizontal bars on top are the enrollment periods of RCT, reported (solid) or imputed (dashed). As shown in this figure the majority of the RCTs started enrolling patients before the publication of the majority of observational studies.

Figure 6

Enrollment periods of RCTs and years of publication of index RCTs and observational studies. Panel a: n-3 PUFA. Panel b: Vitamin E. Red-colored vertices denote index publications of RCTs (i.e., those included in our systematic reviews). Blue-colored vertices (more...)

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, as well as three systematic reviews with meta-analyses (Table 3).

Table 2. Main path articles in the n-3 PUFA example.

Table 2

Main path articles in the n-3 PUFA example.

Table 3. Main path articles in the vitamin E example.

Table 3

Main path articles in the vitamin E example.

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