Abstract
Background
There is an increasing number of meta-analyses including data from non-randomized studies for therapeutic evaluation. We aimed to systematically assess the methods used in meta-analyses including non-randomized studies evaluating therapeutic interventions.
Methods
For this methodological review, we searched MEDLINE via PubMed, from January 1, 2013 to December 31, 2013 for meta-analyses including at least one non-randomized study evaluating therapeutic interventions. Etiological assessments and meta-analyses with no comparison group were excluded. Two reviewers independently assessed the general characteristics and key methodological components of the systematic review process and meta-analysis methods.
Results
One hundred eighty eight meta-analyses were selected: 119 included both randomized controlled trials (RCTs) and non-randomized studies of interventions (NRSI) and 69 only NRSI. Half of the meta-analyses (n = 92, 49 %) evaluated non-pharmacological interventions. “Grey literature” was searched for 72 meta-analyses (38 %). An assessment of methodological quality or risk of bias was reported in 135 meta-analyses (72 %) but this assessment considered the risk of confounding bias in only 33 meta-analyses (18 %). In 130 meta-analyses (69 %), the design of each NRSI was not clearly specified. In 131 (70 %), whether crude or adjusted estimates of treatment effect for NRSI were combined was unclear or not reported. Heterogeneity across studies was assessed in 182 meta-analyses (97 %) and further explored in 157 (84 %). Reporting bias was assessed in 127 (68 %).
Conclusions
Some key methodological components of the systematic review process—search for grey literature, description of the type of NRSI included, assessment of risk of confounding bias and reporting of whether crude or adjusted estimates were combined—are not adequately carried out or reported in meta-analyses including NRSI.
Keywords: Meta-analyses, Therapeutic evaluation, Non-randomized studies, Reporting
Background
Randomized controlled trials (RCTs) are considered the gold standard for evidence-based medicine because they are designed to minimize the risk of bias [1]. However, the applicability of their results has been criticized because of restrictive selection criteria, with, commonly, exclusion of older adults and people with co-morbidities or severe disease [2–4]. Also, conducting an RCT is sometimes impossible or inappropriate (eg, when studying rare or long-term events) [1, 3, 5], which results in critical information gaps.
In contrast, observational studies, the overarching term for all non-experimental non-randomized studies (including cohort, case–control, and cross-sectional studies) [6], generally are more likely to reflect clinical practice in real life because of their broader range of participants, longer follow-up time, and lower costs than RCTs [7–10]. With the aim of generating evidence that will guide healthcare decisions, the field of comparative effectiveness research (CER) emphasizes the need to incorporate data from observational studies to complement RCTs [8, 11–16]. A comprehensive assessment in 2009 indicated that 54 % of CER studies had an observational study design [17]. Therefore, an increasing number of systematic reviews and meta-analyses are including data from non-randomized studies to assess therapeutic interventions.
Similar to systematic reviews of RCTs, reviews including non-randomized studies are expected to follow the general recommendations for good conduct, such as retrieving all relevant studies and assessing their risk of bias. However, some elements should be adapted specifically to the inclusion of non-randomized studies because their study designs inherently differ from RCTs [7, 9, 14, 18–23]. Lacking randomization, they are likely subject to confounding bias, which results in an imbalance in prognostic factors associated with the outcome of interest that may severely compromise the validity of their results [24].
Previous methodological reviews evaluating systematic reviews including observational studies exist [25–28]. However, these studies have a different objective. One assessed the main characteristics of all systematic reviews indexed in Medline on November 2004 whatever the type of included studies (ie, therapeutic, epidemiological, prognostic or diagnostic studies) [27]. Two others focused on the methods and reporting of harms in systematic reviews of adverse events [26, 28]. The last one was in the field of psychiatry and did not concern therapeutic evaluation but assessment of prevalence or association [25]. Further, none of these previous reviews has evaluated the specific methodological problems raised by the inclusion of non-randomized studies.
In this study, we performed a methodological review of meta-analyses including non-randomized studies of interventions (NRSI) to evaluate key methodological components common to all meta-analyses and those specifically related to the inclusion of non-randomized studies.
Methods
Study design
This is a methodological review of meta-analyses including NRSI for therapeutic evaluation. For clarity and consistency, we refer to this article as a “methodological review”, the systematic reviews with meta-analyses included in this methodological review as “meta-analyses”, and the studies included in these meta-analyses as “studies”.
Search strategy
Our goal was not to create an exhaustive list of all meta-analyses that include NRSI but rather to identify a relatively representative sample of recently published meta-analyses that a health professional would most likely encounter when searching for meta-analyses. We therefore searched MEDLINE via PubMed because of its wide use among health professionals, combining keywords and MeSH terms for NRSI, systematic reviews, and meta-analyses (Appendix 1). The search was conducted on January 7, 2014 and restricted to the year 2013.
Eligibility criteria
To be eligible, a meta-analysis had to examine a therapeutic or preventive intervention (such as vaccines) for efficacy or safety, include data from at least one NRSI, and be published in 2013. We excluded meta-analyses that included studies without a comparison group and meta-analyses of etiological assessment. When it was difficult to distinguish an etiological from a therapeutic evaluation, we agreed to include the former if the authors considered the inclusion of RCTs in their meta-analysis. To illustrate: a meta-analysis that investigated the association of the use of statins and risk of cancer would was considered a therapeutic evaluation if the authors planned to include RCTs. Individual patient data meta-analyses were also excluded, as were non-randomized studies that conducted a meta-analysis of the literature as secondary analysis. Finally, we did not include meta-analyses published in a language other than English or those for which the full text was not available.
Selection of relevant meta-analyses
The selection of relevant meta-analyses was conducted in 2 steps. In the first step, one reviewer (CR) excluded clearly irrelevant studies based on the title, abstract, and full text, then, a second reviewer (TF) performed the final selection, discussing all doubtful cases with a third reviewer (AD).
Data extraction
The data extraction form for this methodological review was developed from the MOOSE statement for reporting meta-analyses that include observational studies [29], the PRISMA statement for reporting systematic reviews and meta-analyses of studies evaluating healthcare interventions [30, 31], and the AMSTAR measurement tool for assessing the methodological quality of systematic reviews [32]. The data extraction form was tested by one reviewer (TF) with 10 studies before data extraction commenced.
Two reviewers (TF, CR) independently extracted all data in duplicate, resolving discrepancies with a third reviewer (AD) if necessary. The following characteristics were extracted from the full text and online appendix of each meta-analysis:
General characteristics: We collected whether the journal was a specialty or a general journal, the location of the corresponding author, and the medical area. We verified whether the meta-analysis was registered on the international prospective register of systematic reviews by the University of York’s Centre for Reviews and Dissemination (PROSPERO). We collected whether epidemiologists or statisticians were involved, relying on the definition given by Delgado-Rodriguez et al.[33] and assessed whether the authors reported the funding sources and declared conflict of interests. We assessed whether the meta-analyses evaluated a pharmacological or non-pharmacological intervention. Non-pharmacological interventions were classified as surgical procedures or other interventions. We also assessed the type of studies included: only NRSI or both NRSI and RCTs.
- Systematic review methods:
- ▪Search strategy: We collected how many and which electronic databases were searched, and whether the search strategy for at least one database was provided. We collected whether reference lists and journals were hand-searched and whether the authors searched for grey literature, and if yes, how: search of registries (eg, ClinicalTrials.gov), conference abstracts, or contacting experts. We assessed whether the authors restrict their searches by language.
- ▪Study selection and data extraction process: We assessed whether study selection and data extraction were conducted in duplicate.
- ▪Contact of the study authors: We noted whether it was mentioned that study authors were contacted for clarification or additional results.
- ▪Methodological quality/risk of bias assessment: We assessed whether methodological quality or risk of bias assessment was conducted, what tools were used, and whether the assessment was conducted in duplicate.
- Meta-analysis methods:
- ▪Studies combined: We assessed the types of NRSI included. NRSI were categorized as concurrent (prospective) cohort, nonconcurrent (retrospective) cohort, case–control, or historically controlled studies according to the definition by Ioannidis et al. [21]. We also assessed whether the authors combined the results from NRSI and RCTs and whether they combined results from different types of NRSI (eg, cohort and case–control studies).
- ▪Meta-analysis model: We collected whether the authors used crude or adjusted estimates for NRSI and whether they used fixed- or random-effects models to pool the data. For adjusted estimates, we also collected whether the confounding factors taken into account were listed.
- ▪Assessment and exploration of heterogeneity: We collected whether and how the authors assessed heterogeneity and whether they conducted meta-regression, subgroup, or sensitivity analyses to explore heterogeneity.
- ▪Assessment of reporting bias: We collected information on whether the authors assessed reporting bias, and how.
Statistical analysis
The analysis of the data consisted of descriptive statistics, providing numbers and percentages for qualitative variables and median (minimum, maximum, or interquartile range) for quantitative variables. The results were stratified for meta-analyses including only NRSI and those including both NRSI and RCTs. We did not assess statistical differences between these strata. Statistical analysis involved use of R 3.0.2. (R Core Team [2013]. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL: http://www.R-project.org/).
Results
Study selection
Our MEDLINE search identified 3602 citations; Among the 341 potentially relevant meta-analyses, 188 were eligible for this review (Fig. 1). Complete references for the included meta-analyses and meta-analyses excluded are in Appendixes 2 and 3, respectively.
Fig. 1.
Study selection flowchart
General characteristics (Table 1)
Table 1.
General characteristics of therapeutic meta-analyses published in 2013 and including non-randomized studies of intervention (n = 188)
| Characteristic | Included NRSI only | Included NRSI&RCTs | All meta-analyses |
|---|---|---|---|
| (n = 69) | (n = 119) | (n = 188) | |
| No (%) | No (%) | No (%) | |
| Journal type | |||
| Specialty | 59 (86) | 99 (83) | 158 (84) |
| General | 10 (14) | 20 (17) | 30 (16) |
| Location of corresponding author | |||
| Asia | 26 (38) | 38 (32) | 64 (34) |
| Europe | 22 (32) | 39 (33) | 61 (32) |
| North-America | 18 (26) | 33 (28) | 51 (27) |
| Other | 3 (4) | 9 (7) | 12 (7) |
| Medical area | |||
| Surgery | 21 (30) | 28 (24) | 49 (26) |
| Cardiology | 8 (12) | 25 (21) | 33 (18) |
| Oncology | 6 (9) | 19 (16) | 25 (13) |
| Other | 34 (49) | 47 (39) | 81 (43) |
| Type of intervention | |||
| Pharmacological | 36 (52) | 56 (47) | 92 (49) |
| Non-pharmacological | 32 (46) | 60 (50) | 92 (49) |
| Surgical procedures | 30 (43) | 44 (37) | 74 (39) |
| Other | 2 (3) | 16 (13) | 18 (10) |
| Both pharmacological and non-pharmacological | 1 (1) | 3 (3) | 4 (2) |
| Epidemiologists or statisticians involved | 17 (25) | 19 (16) | 36 (19) |
| Declaration of conflict of interests | 64 (93) | 102 (86) | 166 (88) |
| Potential conflict of interests | 9 (13) | 17 (14) | 26 (14) |
| Funding source | |||
| Public | 30 (43) | 36 (30) | 66 (35) |
| No specific funding | 10 (14) | 29 (24) | 39 (21) |
| Private | 2 (3) | 7 (6) | 9 (5) |
| Both public and private | 3 (4) | 2 (2) | 5 (3) |
| Not reported/unclear | 24 (35) | 45 (38) | 69 (37) |
| Registration on PROSPERO | 0 | 3 (3) | 3 (2) |
NRSI non-randomized studies of intervention; RCTs randomized controlled trials
Among the 188 included meta-analyses, 49 (26 %) were of surgery, 33 (18 %) cardiology, and 25 (13 %) oncology. Half of the meta-analyses assessed non-pharmacological interventions (n = 92, 49 %); 74 involved surgical procedures. Approximately one third (n = 69, 37 %) included only NRSI, and two thirds included both NRSI and RCTs (n = 119, 63 %).
In total, 36 meta-analyses (19 %) involved epidemiologists or statisticians. Conflict of interest was declared in 166 (88 %), with 26 reporting a potential conflict of interest. About one-third of the meta-analyses did not report a source of funding (n = 69, 37 %).
Systematic review methods (Table 2)
Table 2.
Systematic review methods of therapeutic meta-analyses published in 2013 and including non-randomized studies (n = 188)
| Characteristic | Included NRSI only | Included NRSI&RCTs | All Meta-analyses |
|---|---|---|---|
| (n = 69) | (n = 119) | (n = 188) | |
| No (%) | No (%) | No (%) | |
| Search strategy | |||
| No. of electronic databases searched, median [IQR] | 3 [2–4] | 3 [3, 4] | 3 [3, 4] |
| > 2 databases searched | 51 (74) | 96 (81) | 147 (78) |
| Electronic databases searcheda | |||
| Medline/PubMed/Ovid | 69 (100) | 118 (99) | 187 (99) |
| EMBASE | 52 (75) | 97 (82) | 149 (79) |
| Cochrane | 45 (65) | 81 (68) | 126 (67) |
| Web of science/web of knowledge | 14 (20) | 22 (18) | 36 (19) |
| Time-frame of search strategy reported | 62 (90) | 109 (92) | 171 (91) |
| Time end of search-publication date (months), median [min-max] | 10 [0–24] | 9 [1–51] | 10 [0–51] |
| Search strategy provided for at least one database | 18 (26) | 44 (37) | 62 (33) |
| Searched reference lists for relevant studies | 57 (83) | 105 (88) | 162 (86) |
| Hand searched journals | 5 (7) | 7 (6) | 12 (6) |
| Searched for grey literaturea | 23 (33) | 49 (41) | 72 (38) |
| Conference abstracts | 14 (20) | 27 (23) | 41 (22) |
| Registries (eg, ClinicalTrials.gov) | 8 (12) | 25 (21) | 33 (18) |
| Experts | 6 (9) | 9 (8) | 15 (8) |
| No restriction by language reported | 20 (29) | 62 (52) | 82 (44) |
| Study selection | |||
| Duplicate study selection | 47 (68) | 84 (71) | 131 (70) |
| Methodological quality/risk of bias | |||
| Assessment of MQ/RoB | 47 (68) | 88 (74) | 135 (72) |
| Tools used for RCTsa | |||
| Cochrane RoB Tool [41] | NA | 42 (35) | NA |
| Jadad scale [42] | NA | 22 (18) | NA |
| GRADE [43] | NA | 9 (8) | NA |
| Other | NA | 21 (18) | NA |
| Authors made their own tool | NA | 3 (3) | NA |
| Unclear | NA | 7 (6) | NA |
| Tools used for NRSIa | |||
| Newcastle-Ottawa scale [44] | 25 (36) | 43 (36) | 68 (36) |
| GRADE [43] | 5 (7) | 8 (7) | 13 (7) |
| Cochrane RoB Tool [41] | 3 (4) | 7 (6) | 10 (5) |
| Other tools | 13 (19) | 24 (20) | 37 (20) |
| Authors made their own tool | 6 (9) | 6 (5) | 12 (6) |
| Unclear | 3 (4) | 9 (8) | 12 (6) |
| Confounding taken into account in risk of bias | 13 (19) | 20 (17) | 33 (18) |
| Same tool used for RCTs and NRSI | NA | 27 (23) | NA |
| Duplicate MQ/RoB assessment | 30/47 (64) | 57/88 (65) | 87/135 (64) |
| Data extraction | |||
| Duplicate data extraction | 52 (75) | 86 (72) | 138 (73) |
| Contact authors for clarification or additional results | 18 (26) | 43 (36) | 61 (32) |
Data are no. (%), unless indicated. IQR interquartile range; MQ methodological quality; NRSI non-randomized studies of interventions; RCTs randomized controlled trials; Cochrane RoB Cochrane risk of bias tool; NA Not applicable
aMore than one item could have been reported for each meta-analysis
Literature search
Overall, all but one of the meta-analyses reported the search of at least 1 electronic database and 147 (78 %) reported the search of > 2 electronic databases. One third provided the search strategy for each database (n = 62, 33 %). MEDLINE, Embase, and the Cochrane Library were most frequently searched (187 [99 %], 149 [79 %], and 126 (67 %) meta-analyses, respectively). In addition to the search of electronic databases, 162 meta-analyses (86 %) reported screening the reference lists of included studies, and 12 (6 %) reported hand-searching journals. About one-third of the meta-analyses (n = 72, 38 %) reported searching for grey literature: 41 (22 %) conference abstracts, 33 (18 %) registries, and 15 (8 %) contacted experts. For 82 meta-analyses (44 %), the authors reported that they did not restrict their searches by language.
Methodological quality/risk of bias assessment
Methodological quality or risk of bias of included studies was assessed in 135 (72 %) meta-analyses.
For the 119 meta-analyses including RCTs and NRSI, risk of bias was assessed in 88 (74 %) with 4 assessing risk of bias for RCTs only. RCTs were assessed with the Cochrane Risk of Bias tool in 42 (35 %) meta-analyses. The assessment of risk of bias involved the same tool for both RCTs and NRSI in 27 (23 %) meta-analyses. For the assessment of NRSI, a variety of tools were used. The most frequently used tool was the Newcastle-Ottawa Scale (n = 68). GRADE and the Cochrane Collaboration Risk of Bias Tool were used in 13 and 10 meta-analyses, respectively. In 37 meta-analyses, authors used other tools; in 12, they developed their own tools; and in 12, they were unclear about the methods used for assessing methodological quality/risk of bias. Overall, the authors have considered the risk of confounding bias in their risk of bias assessment in 33 meta-analyses (18 %). Of the 135 meta-analyses with an assessment of risk of bias, 87 (64 %) reported having performed it in duplicate.
Meta-analysis methods (Table 3)
Table 3.
Meta-analysis methods of therapeutic meta-analyses published in 2013 and including non-randomized studies (n = 188)
| Characteristic | Included NRSI only | Included NRSI&RCTs | All meta-analyses |
|---|---|---|---|
| (n = 69) | (n = 119) | (n = 188) | |
| No (%) | No (%) | No (%) | |
| Studies combined | |||
| Type of studies included | |||
| Only prospective cohort studies | 2 (3) | 3 (3) | 5 (3) |
| Only cohort studies | 18 (26) | 34 (29) | 52 (28) |
| Including also case–control studies | 18 (26) | 28 (23) | 46 (24) |
| Including all types of NRSI | 5 (7) | 18 (15) | 23 (12) |
| Other | 28 (41) | 39 (33) | 67 (36) |
| “Observational studies” | 6 (9) | 22 (18) | 28 (15) |
| “Prospective and retrospective studies” | 11 (16) | 12 (10) | 23 (12) |
| “Retrospective studies” | 11 (16) | 5 (4) | 16 (9) |
| Did not clearly report design for each study | 43 (62) | 87 (73) | 130 (69) |
| Meta-analysis combining results of NRSI and RCTs | NA | 88 (74) | NA |
| Results also presented separately | NA | 44/88 (50) | NA |
| Meta-analysis combining studies of different designs | 39 (57) | 61 (51) | 100 (53) |
| Meta-analysis model | |||
| Network meta-analysis | 0 | 2 (2) | 2 (1) |
| Crude or adjusted estimates used | |||
| Combined crude and adjusted estimates | 10 (14) | 12 (10) | 22 (12) |
| Adjusted | 8 (12) | 13 (11) | 21 (11) |
| Both crude and adjusted estimates separately | 4 (6) | 4 (3) | 8 (4) |
| Crude | 2 (3) | 4 (3) | 6 (3) |
| Not reported/unclear | 45 (65) | 86 (72) | 131 (70) |
| If adjusted, list of confounding factors | 15/22 (68) | 19/29 (66) | 34/51 (67) |
| Type of model | |||
| Random-effects model | 39 (57) | 56 (47) | 95 (50) |
| Fixed-effects model, unless high heterogeneity, then random-effects model | 19 (28) | 33 (28) | 52 (28) |
| Both fixed- and random-effects models | 5 (7) | 21 (18) | 26 (14) |
| Fixed-effects model | 3 (4) | 6 (5) | 9 (5) |
| Not reported/unclear | 3 (4) | 3 (3) | 6 (3) |
| Heterogeneity assessment & exploration | |||
| Heterogeneity assesseda | 66 (96) | 116 (97) | 182 (97) |
| I2 | 57 (83) | 107 (90) | 164 (87) |
| Cochran Q χ2 test | 41 (59) | 74 (62) | 115 (61) |
| τ2 | 4 (6) | 2 (2) | 6 (3) |
| Heterogeneity exploreda | 54 (82) | 103 (87) | 157 (84) |
| Meta-regression analysis | 13 (19) | 21 (18) | 34 (18) |
| Subgroup analysis | 44 (64) | 82 (69) | 126 (67) |
| Sensitivity analysis | 35 (51) | 74 (62) | 109 (58) |
| Reporting bias assessmenta | 49 (71) | 78 (66) | 127 (68) |
| Standard funnel plot | 41 (59) | 70 (59) | 111 (59) |
| Egger’s test | 32 (46) | 36 (30) | 68 (36) |
| Begg’s test | 18 (26) | 24 (20) | 42 (22) |
| Among MAs with ≥10 studies, reporting bias assessed | 24/29 (83) | 58/76 (76) | 82/105 (78) |
MAs meta-analyses; NRSI non-randomized studies of intervention; RCTs randomized controlled trials
aMore than one item could have been reported for each meta-analysis
Studies combined
For 130 meta-analyses (69 %), the authors did not clearly report the design for each individual study. Among the meta-analyses that included both NRSI and RCTs (n = 119), for 88 (74 %), the results of NRSI and RCTs were combined.
Concerning NRSI combined, 52 meta-analyses (28 %) included only cohort studies and 5 only prospective cohort studies; 46 meta-analyses (24 %) combined cohort and case–control studies, and 23 (12 %) included all types of NRSI. The other 67 meta-analyses (36 %) included “observational studies” (without further details) (n = 28, 15 %), “prospective and retrospective studies” (n = 23, 12 %), and only “retrospective studies” (n = 16, 9 %).
Crude or adjusted estimates used for NRSI
For 131 meta-analyses (70 %), whether crude or adjusted estimates of treatment effect from the NRSI were used for the meta-analysis was unclear or not reported. For the remaining meta-analyses, the authors reported combining crude and adjusted estimates for 22 (12 %), only adjusted estimates for 21 (11 %), and only crude estimates for 6 (3 %). For 8 meta-analyses (4 %), the authors extracted both the crude and adjusted estimates and used them separately in 2 meta-analyses. Among the 51 meta-analyses involving adjusted estimates, 17 (33 %) did not report the confounding factors adjusted for.
Meta-analysis model
A random-effects model was used for half of the meta-analyses (n = 95). For 52 (28 %), a fixed-effects model was used primarily but then replaced with a random-effects model if high heterogeneity was observed in the model. For 26 meta-analyses (14 %), the authors used both fixed- and random-effects models, and for 9 (5 %), a fixed-effects model. The type of model was not reported or was unclear for 6 meta-analyses (3 %). We found 2 network meta-analyses (1 %).
Heterogeneity assessment
Almost all meta-analyses assessed heterogeneity (n = 182, 97 %). The I2 statistic was used in 164 meta-analyses (87 %), Cochran Q χ2 test in 115 (61 %), and between-study variance τ2 in 6 (3 %). Heterogeneity was explored in 157 meta-analyses (84 %) by subgroup analyses (n = 126, 67 %), sensitivity analyses (n = 109, 58 %) and meta-regression analyses (n = 34, 18 %).
For 44 of 88 (50 %) meta-analyses combining results from RCTs and NRSI, a subgroup or sensitivity analysis was based on the type of study (RCT vs NRSI). For 28 meta-analyses (15 %), subgroup or sensitivity analyses were based on the type of NRSI included.
Reporting bias assessment
Reporting bias was assessed in 127 meta-analyses (68 %) by standard funnel plots (n = 111, 59 %), Egger’s test (n = 68, 36 %), or Begg’s test (n = 42, 22 %). Overall, 82 of the 105 meta-analyses (78 %) including 10 or more studies reported having assessed reporting bias.
Discussion
We systematically assessed key methodological components of a large sample of therapeutic meta-analyses including NRSI in a variety of medical areas. Our results highlight some important methodological shortcomings. Only 38 % of the meta-analyses reported having searched for grey literature. Specific points related to the inclusion of NRSI raise concerns, with 69 % of the meta-analyses not reporting the study design of the included NRSI, and 70 % not reporting whether crude or adjusted estimates were combined.
Strengths and limitations of study
To the best of our knowledge, no previous study has comprehensively assessed both key methodological components common to all systematic reviews and elements specific to the inclusion of non-randomized studies. Other studies that previously evaluated methods or reporting of systematic reviews including NRSI concentrated on the reporting of harms [26, 28] and on systematic reviews in psychiatric epidemiology [25].
Our study has some limitations. The representativeness of our sample could be debated because we searched for studies in only one online database (MEDLINE), and limited our selection to meta-analyses in English. In addition, for the assessment of the methods, we depended completely on the reporting; we did not assess protocols or contact the authors if methods were not clearly reported. Even though poor reporting does not necessarily reflect poor conduct, it may severely limit the reader’s comprehension of the systematic review process [34].
Before being able to apply the results of any meta-analysis to patient care, health professionals need to evaluate the credibility of the methods of the meta-analysis [35]. One of the key methodological elements is the search for relevant studies. Because not all studies (and particularly those with negative results) are published in scientific journals, a meta-analysis must involve a search for grey literature to try to avoid such publication bias (a type of reporting bias) [24, 35]. However, we found that only 38 % of our meta-analyses reported having searched for grey literature. Because of no mandatory registration for NRSI as for RCTs, most NRSI are not registered, so searching for grey literature of NRSI is difficult [36]. However, a recent study found that for 32 % of the observational studies registered at ClinicalTrials.gov, unpublished results could be retrieved [37]. In contrast, we found that many meta-analyses assessed reporting bias (68 %). Reviewers may have compensated for the absence of searching for grey literature by assessing reporting bias. Evaluating reporting bias does not exempt the reviewers from searching for grey literature because the assessment of Funnel plot asymmetry may be subjective and statistical methods to test for asymmetry of the plot may lack power [38, 39].
Another critical part of the systematic review process is assessing the methodological quality or risk of bias of the studies included, because the validity of the meta-analysis could be questionable with problems in the design and conduct of individual studies [40]. We found that 72 % of our meta-analyses reported having assessed the methodological quality or risk of bias but only 33 (18 %) considered the risk of confounding bias in their assessment. The Cochrane Collaboration has recognized the need to improve the assessment of risk of bias for NRSI and is currently developing a tool for this.
Finally, we found specific issues related to the inclusion of NRSI. In 69 % of the meta-analyses, the study design for each included study was unclear. The risk of bias may vary depending on the type of NRSI, with case–control studies generally considered as having a higher risk of bias than cohort studies. A description of the type of studies included in the meta-analysis is crucial. In addition, NRSI are prone to confounding: an imbalance in prognostic factors associated with the outcome of interest [24]. NRSI are expected to at least present adjusted estimates from multivariate analyses [3, 4]. Many of our meta-analyses (70 %) did not report or were unclear about whether the crude or adjusted estimates of NRSI were combined. Among the meta-analyses involving adjusted estimates, 33 % did not report the confounding factors adjusted for. This information was likely poorly reported in the individual studies, but then the reviewers should contact the authors for clarification or report it clearly in the meta-analysis.
Conclusions
Some key methodological components of the systematic review process – search for grey literature, description of the type of NRSI included, assessment of risk of confounding bias and reporting of whether crude or adjusted estimates were combined—are not adequately reported in meta-analyses including NRSI. Attention should be paid to improving these elements in such meta-analyses to have an increased confidence in their results.
Ethics
Not applicable. This article reports a meta-research study.
Consent
Not needed. This study does not include human participants.
Availability of supporting data
Data are available upon request for academic researchers.
Acknowledgements
Philippe Ravaud is director of the French EQUATOR Centre and a member of the EQUATOR Network Steering Group.
Sources of funding
The researchers did not receive external sources of funding.
Abbreviations
- CER
comparative effectiveness research
- NRSI
non-randomized studies of interventions
- RCT
randomized controlled trial
- RoB Tool
Risk of Bias tool
Appendices
Appendix 1 Search strategy
Pubmed Search Equation
| 1. | “observational” [tiab] |
| 2. | “cohort” [tiab] |
| 3. | cohort studies [mh] |
| 4. | “epidemiologic” [tiab] |
| 5. | “epidemiological” [tiab] |
| 6. | “systematic review” [tiab] |
| 7. | “systematic reviews” [tiab] |
| 8. | “meta-analysis” [tiab] |
| 9. | “meta-analyses” [tiab] |
| 10. | meta analysis [pt] |
| 11. | “overview” [tiab] |
| 12. | #1 OR #2 OR #3 OR #4 OR #5 |
| 13. | #6 OR #7 OR #8 OR #9 OR #10 OR #11 |
| 14. | #12 AND #13 |
Date of search: 7 January 2014
Search limits: Published between 1 January 2013 and 31 December 2013.
Citations retrieved: 3602.
Appendix 2 List of included meta-analyses (N = 188)
Meta-analyses including observational studies and randomized controlled trials (N = 119)
| Study ID | Reference of included citation |
| 35 | Abdelaal, E., S. V. Rao, et al. (2013). "Same-day discharge compared with overnight hospitalization after uncomplicated percutaneous coronary intervention: a systematic review and meta-analysis." JACC Cardiovasc Interv6(2): 99–112. |
| 51 | Abubakar, I., L. Pimpin, et al. (2013). "Systematic review and meta-analysis of the current evidence on the duration of protection by bacillus Calmette-Guerin vaccination against tuberculosis." Health Technol Assess17(37): 1–372, v-vi. |
| 71 | Agarwal, V., A. Briasoulis, et al. (2013). "Effects of renin-angiotensin system blockade on mortality and hospitalization in heart failure with preserved ejection fraction." Heart Fail Rev18(4): 429–437. |
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| 423 | Bang, C. N., A. M. Greve, et al. (2013). "The preventive effect of statin therapy on new-onset and recurrent atrial fibrillation in patients not undergoing invasive cardiac interventions: a systematic review and meta-analysis." Int J Cardiol167(3): 624–630. |
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| 1115 | Chionh, C. Y., S. S. Soni, et al. (2013). "Use of peritoneal dialysis in AKI: a systematic review." Clin J Am Soc Nephrol8(10): 1649–1660. |
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| 1375 | De Luca, G., A. Schaffer, et al. (2013). "Comprehensive meta-analysis of radial vs femoral approach in primary angioplasty for STEMI." Int J Cardiol168(3): 2070–2081. |
| 1451 | Deng, Z., S. Zhang, et al. (2013). "Can statins reduce risk of lung cancer, especially among elderly people? A meta-analysis." Chin J Cancer Res25(6): 679–688. |
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| 2459 | He, M. M., W. J. Wu, et al. (2013). "S-1-Based Chemotherapy versus Capecitabine-Based Chemotherapy as First-Line Treatment for Advanced Gastric Carcinoma: A Meta-Analysis." PLoS One8(12): e82798. |
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| 2569 | Ho, E. T., G. Wong, et al. (2013). "Once-daily extended-release versus twice-daily standard-release tacrolimus in kidney transplant recipients: a systematic review." Transplantation95(9): 1120–1128. |
| 2661 | Hu, J., J. Qu, et al. (2013). "Allograft versus autograft for anterior cruciate ligament reconstruction: an up-to-date meta-analysis of prospective studies." Int Orthop37(2): 311–320. |
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| 2883 | Jin, H. M., L. L. Guo, et al. (2013). "Effect of prolonged weekly hemodialysis on survival of maintenance hemodialysis patients: a meta-analysis of studies." Nephron Clin Pract123(3–4): 220–228. |
| 2899 | Johnson, L. N., I. E. Sasson, et al. (2013). "Does intracytoplasmic sperm injection improve the fertilization rate and decrease the total fertilization failure rate in couples with well-defined unexplained infertility? A systematic review and meta-analysis." Fertil Steril100(3): 704–711. |
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| 2975 | Kalam, K. and T. H. Marwick (2013). "Role of cardioprotective therapy for prevention of cardiotoxicity with chemotherapy: a systematic review and meta-analysis." Eur J Cancer49(13): 2900–2909. |
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| 3540 | Li, Q., Z. Zhang, et al. (2013). "Drug-eluting stents or coronary artery bypass grafting for unprotected left main coronary artery disease: a meta-analysis of four randomized trials and seventeen observational studies." Trials14: 133. |
| 3546 | Li, S., Y. Liu, et al. (2013). "Association between non-steroidal anti-inflammatory drug use and melanoma risk: a meta-analysis of 13 studies." Cancer Causes Control24(8): 1505–1516. |
| 3564 | Li, Y., H. Zhang, et al. (2013). "Neuroendoscopic Surgery versus External Ventricular Drainage Alone or with Intraventricular Fibrinolysis for Intraventricular Hemorrhage Secondary to Spontaneous Supratentorial Hemorrhage: A Systematic Review and Meta-Analysis." PLoS One8(11): e80599. |
| 3576 | Liao, M., J. Huang, et al. (2013). "Transarterial chemoembolization in combination with local therapies for hepatocellular carcinoma: a meta-analysis." PLoS One8(7): e68453. |
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| 4223 | Moran, P. S., M. O'Neill, et al. (2013). "Robot-assisted radical prostatectomy compared with open and laparoscopic approaches: a systematic review and meta-analysis." Int J Urol20(3): 312–321. |
| 4263 | Moyses, H. E., M. J. Johnson, et al. (2013). "Early parenteral nutrition and growth outcomes in preterm infants: a systematic review and meta-analysis." Am J Clin Nutr97(4): 816–826. |
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| 4359 | Navarese, E. P., P. A. Gurbel, et al. (2013). "Optimal timing of coronary invasive strategy in non-ST-segment elevation acute coronary syndromes: a systematic review and meta-analysis." Ann Intern Med158(4): 261–270. |
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| 4411 | Ni, X., J. Ma, et al. (2013). "Meta-analysis on the association between non-steroidal anti-inflammatory drug use and ovarian cancer." Br J Clin Pharmacol75(1): 26–35. |
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| 5670 | Singh, S., P. P. Singh, et al. (2013). "Anti-diabetic medications and risk of pancreatic cancer in patients with diabetes mellitus: a systematic review and meta-analysis." Am J Gastroenterol108(4): 510–519; quiz 520. |
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| 5988 | Tan, M., X. Song, et al. (2013). "Statins and the risk of lung cancer: a meta-analysis." PLoS One8(2): e57349. |
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Meta-analyses including only observational studies (N = 69)
| Study ID | Reference of included citation |
| 93 | Ahmed, S., R. K. Shahid, et al. (2013). "Should noncurative resection of the primary tumour be performed in patients with stage iv colorectal cancer? A systematic review and meta-analysis." Curr Oncol20(5): e420-441. |
| 113 | Al Rawahi, T., A. D. Lopes, et al. (2013). "Surgical cytoreduction for recurrent epithelial ovarian cancer." Cochrane Database Syst Rev2: CD008765. |
| 151 | Alhazmi, A., E. Stojanovski, et al. (2013). "The association between dietary patterns and type 2 diabetes: a systematic review and meta-analysis of cohort studies." J Hum Nutr Diet. |
| 227 | Andrade, J. G., M. W. Deyell, et al. (2013). "Risk of bleeding on triple antithrombotic therapy after percutaneous coronary intervention/stenting: a systematic review and meta-analysis." Can J Cardiol29(2): 204–212. |
| 269 | Antoniou, G. A., G. S. Georgiadis, et al. (2013). "A meta-analysis of outcomes of endovascular abdominal aortic aneurysm repair in patients with hostile and friendly neck anatomy." J Vasc Surg57(2): 527–538. |
| 375 | Bacchetti, S., S. Bertozzi, et al. (2013). "Surgical treatment and survival in patients with liver metastases from neuroendocrine tumors: a meta-analysis of observational studies." Int J Hepatol2013: 235040. |
| 433 | Bao, F., P. Ye, et al. (2013). "Segmentectomy or lobectomy for early stage lung cancer: a meta-analysis." Eur J Cardiothorac Surg. |
| 459 | Bartels, S. A., T. J. Gardenbroek, et al. (2013). "Systematic review and meta-analysis of laparoscopic versus open colectomy with end ileostomy for non-toxic colitis." Br J Surg100(6): 726–733. |
| 481 | Bavinger, C., E. Bendavid, et al. (2013). "Risk of cardiovascular disease from antiretroviral therapy for HIV: a systematic review." PLoS One8(3): e59551. |
| 491 | Beales, I. L., A. Hensley, et al. (2013). "Reduced esophageal cancer incidence in statin users, particularly with cyclo-oxygenase inhibition." World J Gastrointest Pharmacol Ther4(3): 69–79. |
| 525 | Belkhair, S. and G. Pickett (2013). "One versus double burr holes for treating chronic subdural hematoma meta-analysis." Can J Neurol Sci40(1): 56–60. |
| 559 | Berhan, Y. and A. Berhan (2013). "A meta-analysis of reverse breech extraction to deliver a deeply impacted head during cesarean delivery." Int J Gynaecol Obstet. |
| 627 | Billioud, V., A. C. Ford, et al. (2013). "Preoperative use of anti-TNF therapy and postoperative complications in inflammatory bowel diseases: a meta-analysis." J Crohns Colitis7(11): 853–867. |
| 791 | Brown, K. A., N. Khanafer, et al. (2013). "Meta-analysis of antibiotics and the risk of community-associated Clostridium difficile infection." Antimicrob Agents Chemother57(5): 2326–2332. |
| 916 | Carnuccio, P., J. Jimeno, et al. (2013). "Laparoscopic right colectomy: a systematic review and meta-analysis of observational studies comparing two types of anastomosis." Tech Coloproctol. |
| 990 | Chang, K. H., J. P. Burke, et al. (2013). "Infliximab versus cyclosporine as rescue therapy in acute severe steroid-refractory ulcerative colitis: a systematic review and meta-analysis." Int J Colorectal Dis28(3): 287–293. |
| 1025 | Chatu, S., V. Subramanian, et al. (2013). "The Role of Thiopurines in Reducing the Need for Surgical Resection in Crohn's Disease: A Systematic Review and Meta-Analysis." Am J Gastroenterol. |
| 1063 | Chen, W. K. and C. H. Miao (2013). "The effect of anesthetic technique on survival in human cancers: a meta-analysis of retrospective and prospective studies." PLoS One8(2): e56540. |
| 1065 | Chen, Y., J. J. Guan, et al. (2013). "Outcome of Cervicocranial Artery Dissection with Different Treatments: A Systematic Review and Meta-analysis." J Stroke Cerebrovasc Dis. |
| 1161 | Chu, H., L. Zhao, et al. (2013). "Sulbactam-based therapy for Acinetobacter baumannii infection: a systematic review and meta-analysis." Braz J Infect Dis17(4): 389–394. |
| 1367 | de Cuba, E. M., R. Kwakman, et al. (2013). "Cytoreductive surgery and HIPEC for peritoneal metastases combined with curative treatment of colorectal liver metastases: Systematic review of all literature and meta-analysis of observational studies." Cancer Treat Rev39(4): 321–327. |
| 1399 | De Vecchis, R., C. Esposito, et al. (2013). "Cabergoline use and risk of fibrosis and insufficiency of cardiac valves : Meta-analysis of observational studies." Herz38(8): 868–880. |
| 1621 | Duranton, F., M. E. Rodriguez-Ortiz, et al. (2013). "Vitamin D treatment and mortality in chronic kidney disease: a systematic review and meta-analysis." Am J Nephrol37(3): 239–248. |
| 1675 | El-Hussuna, A., A. Krag, et al. (2013). "The effect of anti-tumor necrosis factor alpha agents on postoperative anastomotic complications in Crohn's disease: a systematic review." Dis Colon Rectum56(12): 1423–1433. |
| 1741 | Eurich, D. T., D. L. Weir, et al. (2013). "Comparative safety and effectiveness of metformin in patients with diabetes mellitus and heart failure: systematic review of observational studies involving 34,000 patients." Circ Heart Fail6(3): 395–402. |
| 1932 | Forst, T., M. Hanefeld, et al. (2013). "Association of sulphonylurea treatment with all-cause and cardiovascular mortality: a systematic review and meta-analysis of observational studies." Diab Vasc Dis Res10(4): 302–314. |
| 1980 | Fu, D., G. Li, et al. (2013). "Comparison of clinical outcome between simultaneous-bilateral and staged-bilateral total knee arthroplasty: a systematic review of retrospective studies." J Arthroplasty28(7): 1141–1147. |
| 2044 | Gandhi, S., N. Narula, et al. (2013). "Meta-analysis: colonoscopic post-polypectomy bleeding in patients on continued clopidogrel therapy." Aliment Pharmacol Ther37(10): 947–952. |
| 2112 | Gedmintas, L., D. H. Solomon, et al. (2013). "Bisphosphonates and risk of subtrochanteric, femoral shaft, and atypical femur fracture: a systematic review and meta-analysis." J Bone Miner Res28(8): 1729–1737. |
| 2196 | Gong, J., L. Zhu, et al. (2013). "Use of thiopurines and risk of colorectal neoplasia in patients with inflammatory bowel diseases: a meta-analysis." PLoS One8(11): e81487. |
| 2343 | Habib, A. G. and D. A. Warrell (2013). "Antivenom therapy of carpet viper (Echis ocellatus) envenoming: effectiveness and strategies for delivery in West Africa." Toxicon69: 82–89. |
| 2441 | Haverkamp, L., T. J. Weijs, et al. (2013). "Laparoscopic total gastrectomy versus open total gastrectomy for cancer: a systematic review and meta-analysis." Surg Endosc27(5): 1509–1520. |
| 2733 | Hyun, M. H., C. H. Lee, et al. (2013). "Systematic review and meta-analysis of robotic surgery compared with conventional laparoscopic and open resections for gastric carcinoma." Br J Surg100(12): 1566–1578. |
| 2795 | Jackson, C., A. Mann, et al. (2013). "Effectiveness of Haemophilus influenzae type b vaccines administered according to various schedules: systematic review and meta-analysis of observational data." Pediatr Infect Dis J32(11): 1261–1269. |
| 2825 | Jamjoom, A. A. and A. B. Jamjoom (2013). "Safety and efficacy of early pharmacological thromboprophylaxis in traumatic brain injury: systematic review and meta-analysis." J Neurotrauma30(7): 503–511. |
| 3030 | Karthikeyan, G., N. B. Senguttuvan, et al. (2013). "Urgent surgery compared with fibrinolytic therapy for the treatment of left-sided prosthetic heart valve thrombosis: a systematic review and meta-analysis of observational studies." Eur Heart J34(21): 1557–1566. |
| 3097 | Khan, A. R., M. Riaz, et al. (2013). "The role of statins in prevention and treatment of community acquired pneumonia: a systematic review and meta-analysis." PLoS One8(1): e52929. |
| 3496 | Li, B. H., X. Ding, et al. (2013). "Meta-analysis of clinical outcomes of intravenous recombinant tissue plasminogen activator for acute ischemic stroke: within 3 h versus 3–4.5 h." Curr Med Res Opin29(9): 1105–1114. |
| 3692 | Liu, X., S. Min, et al. (2013). "Anterior corpectomy versus posterior laminoplasty for multilevel cervical myelopathy: a systematic review and meta-analysis." Eur Spine J. |
| 4032 | Mazza, M., F. D'Ascenzo, et al. (2013). "Drugs for attention deficit-hyperactivity disorder do not increase the mid-term risk of sudden death in children: a meta-analysis of observational studies." Int J Cardiol168(4): 4320–4321. |
| 4335 | Nakamura, M. and H. Nakashima (2013). "Laparoscopic distal pancreatectomy and pancreatoduodenectomy: is it worthwhile? A meta-analysis of laparoscopic pancreatectomy." J Hepatobiliary Pancreat Sci20(4): 421–428. |
| 4375 | Nderitu, P., L. Doos, et al. (2013). "Non-steroidal anti-inflammatory drugs and chronic kidney disease progression: a systematic review." Fam Pract30(3): 247–255. |
| 4528 | O'Neill, M., P. S. Moran, et al. (2013). "Robot-assisted hysterectomy compared to open and laparoscopic approaches: systematic review and meta-analysis." Arch Gynecol Obstet287(5): 907–918. |
| 4679 | Park, H. J., D. W. Kim, et al. (2013). "Staging laparoscopy for the management of early-stage ovarian cancer: a metaanalysis." Am J Obstet Gynecol209(1): 58 e51-58. |
| 4731 | Pazionis, T. J., H. Alradwan, et al. (2013). "A Systematic Review and Meta-Analysis of En-Bloc vs Intralesional Resection for Giant Cell Tumor of Bone of the Distal Radius." Open Orthop J7: 103–108. |
| 5377 | Sarikaya, H., B. R. da Costa, et al. (2013). "Antiplatelets versus anticoagulants for the treatment of cervical artery dissection: Bayesian meta-analysis." PLoS One8(9): e72697. |
| 5496 | Sepehripour, A. H., S. Saso, et al. (2013). "Does off-pump coronary revascularization reduce mortality in re-operative coronary artery surgery? A meta-analysis of observational studies." Perfusion28(4): 340–349. |
| 5528 | Shan, L., P. Hao, et al. (2013). "Benefits of early tracheotomy: a meta-analysis based on 6 observational studies." Respir Care58(11): 1856–1862. |
| 5548 | Sharma, V., S. V. Deo, et al. (2014). "Meta-analysis of staged versus combined carotid endarterectomy and coronary artery bypass grafting." Ann Thorac Surg97(1): 102–109. |
| 5744 | Soeters, H. M., S. Napravnik, et al. (2013). "The effect of tuberculosis treatment on virologic and CD4+ cell count response to combination antiretroviral therapy: a systematic review." AIDS. |
| 5746 | Soeters, H. M., C. Poole, et al. (2013). "The effect of tuberculosis treatment at combination antiretroviral therapy initiation on subsequent mortality: a systematic review and meta-analysis." PLoS One8(10): e78073. |
| 5840 | Steinberg, B. A., V. Hasselblad, et al. (2013). "Dabigatran for periprocedural anticoagulation following radiofrequency ablation for atrial fibrillation: a meta-analysis of observational studies." J Interv Card Electrophysiol37(3): 213–221. |
| 5882 | Su, A. P., N. W. Ke, et al. (2014). "Is laparoscopic approach for pancreatic insulinomas safe? Results of a systematic review and meta-analysis." J Surg Res186(1): 126–134. |
| 5958 | Taioli, E., D. S. Lee, et al. (2013). "Long-term survival in video-assisted thoracoscopic lobectomy vs open lobectomy in lung-cancer patients: a meta-analysis." Eur J Cardiothorac Surg44(4): 591–597. |
| 6040 | Tee, M. C., Y. Cao, et al. (2013). "Effect of bariatric surgery on oncologic outcomes: a systematic review and meta-analysis." Surg Endosc27(12): 4449–4456. |
| 6092 | Thosani, N., S. N. Thosani, et al. (2013). "Reduced risk of colorectal cancer with use of oral bisphosphonates: a systematic review and meta-analysis." J Clin Oncol31(5): 623–630. |
| 6526 | Wang, L., Z. Wu, et al. (2013). "Laparoendoscopic single-site adrenalectomy versus conventional laparoscopic surgery: a systematic review and meta-analysis of observational studies." J Endourol27(6): 743–750. |
| 6621 | Weiss, A. J., S. Zhao, et al. (2013). "A meta-analysis comparing bilateral internal mammary artery with left internal mammary artery for coronary artery bypass grafting." Ann Cardiothorac Surg2(4): 390–400. |
| 6779 | Wu, X. S., P. Dong, et al. (2013). "Combined portal vein resection for hilar cholangiocarcinoma: a meta-analysis of comparative studies." J Gastrointest Surg17(6): 1107–1115. |
| 6843 | Xu, S. B., Y. P. Zhu, et al. (2013). "Patients get more long-term benefit from central pancreatectomy than distal resection: a meta-analysis." Eur J Surg Oncol39(6): 567–574. |
| 6866 | Yakoob, M. Y., B. T. Bateman, et al. (2013). "The risk of congenital malformations associated with exposure to beta-blockers early in pregnancy: a meta-analysis." Hypertension62(2): 375–381. |
| 6912 | Ye, X., J. Fu, et al. (2013). "Dose-risk and duration-risk relationships between aspirin and colorectal cancer: a meta-analysis of published cohort studies." PLoS One8(2): e57578. |
| 6944 | Yoon, J. M., E. G. Cho, et al. (2013). "Antidepressant use and diabetes mellitus risk: a meta-analysis." Korean J Fam Med34(4): 228–240. |
| 7018 | Zhang, H., C. Gao, et al. (2013). "Metformin and reduced risk of hepatocellular carcinoma in diabetic patients: a meta-analysis." Scand J Gastroenterol48(1): 78–87. |
| 7020 | Zhang, H., D. Jiang, et al. (2013). "Use of nonsteroidal anti-inflammatory drugs and bladder cancer risk: a meta-analysis of epidemiologic studies." PLoS One8(7): e70008. |
| 7096 | Zheng, H., S. Xue, et al. (2013). "Meta-analysis of clinical studies comparing coronary artery bypass grafting with percutaneous coronary intervention in patients with end-stage renal disease." Eur J Cardiothorac Surg43(3): 459–467. |
| 7104 | Zheng, Z., W. Liang, et al. (2013). "Liver Transplantation Versus Liver Resection in the Treatment of Hepatocellular Carcinoma: A Meta-Analysis of Observational Studies." Transplantation. |
| 7108 | Zheng, Z., H. Shi, et al. (2013). "Vitamin D supplementation and mortality risk in chronic kidney disease: a meta-analysis of 20 observational studies." BMC Nephrol14: 199. |
| 7130 | Zhou, X., J. L. Du, et al. (2013). "Statin therapy is beneficial for the prevention of atrial fibrillation in patients with coronary artery disease: a meta-analysis." Eur J Pharmacol707(1–3): 104–111. |
Appendix 3: List of excluded meta-analyses (N = 153)
| Reason for exclusion: | |
| Not a therapeutic evaluation (n = 77) | |
| Study ID | Reference of included citation |
| 177 | Almenawer, S. A., I. Bogza, et al. (2013). "The value of scheduled repeat cranial computed tomography after mild head injury: single-center series and meta-analysis." Neurosurgery72(1): 56–62; discussion 63–54. |
| 335 | Atlantis, E., P. Fahey, et al. (2013). "Endogenous testosterone level and testosterone supplementation therapy in chronic obstructive pulmonary disease (COPD): a systematic review and meta-analysis." BMJ Open3(8). |
| 2050 | Gans, I., K. D. Baldwin, et al. (2013). "Treatment and Management Outcomes of Tibial Eminence Fractures in Pediatric Patients: A Systematic Review." Am J Sports Med. |
| 2062 | Garces, S., J. Demengeot, et al. (2013). "The immunogenicity of anti-TNF therapy in immune-mediated inflammatory diseases: a systematic review of the literature with a meta-analysis." Ann Rheum Dis72(12): 1947–1955. |
| 5938 | Suthar, A. B., D. Hoos, et al. (2013). "Integrating antiretroviral therapy into antenatal care and maternal and child health settings: a systematic review and meta-analysis." Bull World Health Organ91(1): 46–56. |
| 7112 | Zhi, X., X. Zhou, et al. (2013). "Practical role of mutation analysis for imatinib treatment in patients with advanced gastrointestinal stromal tumors: a meta-analysis." PLoS One8(11): e79275. |
| 475 | Bauer, S. R., S. E. Hankinson, et al. (2013). "Plasma vitamin D levels, menopause, and risk of breast cancer: dose–response meta-analysis of prospective studies." Medicine (Baltimore)92(3): 123–131. |
| 591 | Bewtra, M., L. M. Kaiser, et al. (2013). "Crohn's disease and ulcerative colitis are associated with elevated standardized mortality ratios: a meta-analysis." Inflamm Bowel Dis19(3): 599–613. |
| 597 | Bhangu, A., D. Nepogodiev, et al. (2013). "Meta-analysis of plasma to red blood cell ratios and mortality in massive blood transfusions for trauma." Injury44(12): 1693–1699. |
| 675 | Bonifazi, M., I. Tramacere, et al. (2013). "Systemic sclerosis (scleroderma) and cancer risk: systematic review and meta-analysis of observational studies." Rheumatology (Oxford)52(1): 143–154. |
| 701 | Bosanquet, D. C., D. A. Harris, et al. (2013). "Systematic review and meta-analysis of intraoperative peritoneal lavage for colorectal cancer staging." Br J Surg100(7): 853–862. |
| 717 | Bougma, K., F. E. Aboud, et al. (2013). "Iodine and mental development of children 5 years old and under: a systematic review and meta-analysis." Nutrients5(4): 1384–1416. |
| 803 | Bryant, A. R., S. B. Wilton, et al. (2013). "Association between QRS duration and outcome with cardiac resynchronization therapy: a systematic review and meta-analysis." J Electrocardiol46(2): 147–155. |
| 1017 | Charidimou, A., P. Kakar, et al. (2013). "Cerebral microbleeds and recurrent stroke risk: systematic review and meta-analysis of prospective ischemic stroke and transient ischemic attack cohorts." Stroke44(4): 995–1001. |
| 1349 | Davies, A., K. P. Singh, et al. (2013). "Treatment outcomes of treatment-naive Hepatitis C patients co-infected with HIV: a systematic review and meta-analysis of observational cohorts." PLoS One8(2): e55373. |
| 1996 | Fumery, M., C. Xiaocang, et al. (2013). "Thromboembolic events and cardiovascular mortality in inflammatory bowel diseases: A meta-analysis of observational studies." J Crohns Colitis. |
| 2066 | Garcia, S., Y. Sandoval, et al. (2013). "Outcomes after complete versus incomplete revascularization of patients with multivessel coronary artery disease: a meta-analysis of 89,883 patients enrolled in randomized clinical trials and observational studies." J Am Coll Cardiol62(16): 1421–1431. |
| 2144 | Gielen, C., O. Dekkers, et al. (2013). "The effects of pre- and postoperative fibrinogen levels on blood loss after cardiac surgery: a systematic review and meta-analysis." Interact Cardiovasc Thorac Surg. |
| 2689 | Huang, Y., R. Chen, et al. (2013). "Association between point-of-care CRP testing and antibiotic prescribing in respiratory tract infections: a systematic review and meta-analysis of primary care studies." Br J Gen Pract63(616): 787–794. |
| 2823 | James, M. T., S. M. Samuel, et al. (2013). "Contrast-induced acute kidney injury and risk of adverse clinical outcomes after coronary angiography: a systematic review and meta-analysis." Circ Cardiovasc Interv6(1): 37–43. |
| 3014 | Kaptoge, S., S. R. Seshasai, et al. (2013). "Inflammatory cytokines and risk of coronary heart disease: new prospective study and updated meta-analysis." Eur Heart J. |
| 3476 | Lemos, E. V., F. P. de la Hoz, et al. (2013). "Carbapenem resistance and mortality in patients with Acinetobacter baumannii infection: systematic review and meta-analysis." Clin Microbiol Infect. |
| 317 | Arregui, M., B. Buijsse, et al. (2014). "Adiponectin and Risk of Stroke: Prospective Study and Meta-analysis." Stroke45(1): 10–17. |
| 367 | Baandrup, L., M. T. Faber, et al. (2013). "Nonsteroidal anti-inflammatory drugs and risk of ovarian cancer: systematic review and meta-analysis of observational studies." Acta Obstet Gynecol Scand92(3): 245–255. |
| 609 | Bhattacharjee, S., R. Bhattacharya, et al. (2013). "Antidepressant use and new-onset diabetes: a systematic review and meta-analysis." Diabetes Metab Res Rev29(4): 273–284. |
| 641 | Blackadar, C. B. (2013). "Systematic review of hepatocellular carcinoma mortality rates among hepatitis B virus-infected renal transplant recipients, with supplemental analyses of liver failure and all-cause mortality." Int J Infect Dis17(1): e24-36. |
| 679 | Bonovas, S., G. Nikolopoulos, et al. (2013). "Bisphosphonate use and risk of colorectal cancer: a systematic review and meta-analysis." Br J Clin Pharmacol76(3): 329–337. |
| 707 | Bosetti, C., V. Rosato, et al. (2013). "Cancer risk for patients using thiazolidinediones for type 2 diabetes: a meta-analysis." Oncologist18(2): 148–156. |
| 771 | Brinton, L. A. and A. S. Felix (2013). "Menopausal hormone therapy and risk of endometrial cancer." J Steroid Biochem Mol Biol. |
| 1071 | Chen, Y. B., Q. Chen, et al. (2013). "Insulin therapy and risk of prostate cancer: a systematic review and meta-analysis of observational studies." PLoS One8(11): e81594. |
| 1143 | Choueiri, T. K., Y. Je, et al. (2013). "Analgesic use and the risk of kidney cancer: A meta-analysis of epidemiologic studies." Int J Cancer. |
| 2415 | Hargreave, M., A. Jensen, et al. (2013). "Fertility treatment and childhood cancer risk: a systematic meta-analysis." Fertil Steril100(1): 150–161. |
| 2443 | Havrilesky, L. J., P. G. Moorman, et al. (2013). "Oral contraceptive pills as primary prevention for ovarian cancer: a systematic review and meta-analysis." Obstet Gynecol122(1): 139–147. |
| 3024 | Karlstad, O., J. Starup-Linde, et al. (2013). "Use of insulin and insulin analogs and risk of cancer - systematic review and meta-analysis of observational studies." Curr Drug Saf8(5): 333–348. |
| 3464 | Lee, S. H., R. C. Chan, et al. (2013). "Use of bisphosphonates and the risk of osteonecrosis among cancer patients: a systemic review and meta-analysis of the observational studies." Support Care Cancer. |
| 3466 | Lee, S. H., S. S. Chang, et al. (2013). "Risk of osteonecrosis in patients taking bisphosphonates for prevention of osteoporosis: a systematic review and meta-analysis." Osteoporos Int. |
| 3933 | Maneiro, J. R., E. Salgado, et al. (2013). "Immunogenicity of monoclonal antibodies against tumor necrosis factor used in chronic immune-mediated Inflammatory conditions: systematic review and meta-analysis." JAMA Intern Med173(15): 1416–1428. |
| 4345 | Namazy, J. A., V. E. Murphy, et al. (2013). "Effects of asthma severity, exacerbations and oral corticosteroids on perinatal outcomes." Eur Respir J41(5): 1082–1090. |
| 4441 | Noel, S. E., A. C. Stoneham, et al. (2013). "Consumption of omega-3 fatty acids and the risk of skin cancers: A systematic review and meta-analysis." Int J Cancer. |
| 4695 | Parsaik, A. K., B. Singh, et al. (2013). "Statins use and risk of depression: A systematic review and meta-analysis." J Affect Disord. |
| 4923 | Pradelli, D., D. Soranna, et al. (2013). "Statins and primary liver cancer: a meta-analysis of observational studies." Eur J Cancer Prev22(3): 229–234. |
| 4971 | Qi, Z. Y., C. Shao, et al. (2013). "Reproductive and exogenous hormone factors in relation to risk of meningioma in women: a meta-analysis." PLoS One8(12): e83261. |
| 4975 | Qin, J., T. Yang, et al. (2013). "Oral contraceptive use and uterine leiomyoma risk: a meta-analysis based on cohort and case–control studies." Arch Gynecol Obstet288(1): 139–148. |
| 4991 | Qu, H., G. R. Sun, et al. (2013). "Clinical risk factors of delayed gastric emptying in patients after pancreaticoduodenectomy: a systematic review and meta-analysis." Eur J Surg Oncol39(3): 213–223. |
| 5015 | Rabenda, V., D. Nicolet, et al. (2013). "Relationship between use of antidepressants and risk of fractures: a meta-analysis." Osteoporos Int24(1): 121–137. |
| 5311 | Salgado, E., J. R. Maneiro, et al. (2013). "Rheumatoid factor and response to TNF antagonists in rheumatoid arthritis: Systematic review and meta-analysis of observational studies." Joint Bone Spine. |
| 5468 | Scosyrev, E., S. Tobis, et al. (2013). "Statin use and the risk of biochemical recurrence of prostate cancer after definitive local therapy: a meta-analysis of eight cohort studies." BJU Int111(3 Pt B): E71-77. |
| 5472 | Scott, I. C., R. Tan, et al. (2013). "The protective effect of alcohol on developing rheumatoid arthritis: a systematic review and meta-analysis." Rheumatology (Oxford)52(5): 856–867. |
| 5644 | Singh, I., S. Rajagopalan, et al. (2013). "Preoperative statin therapy is associated with lower requirement of renal replacement therapy in patients undergoing cardiac surgery: a meta-analysis of observational studies." Interact Cardiovasc Thorac Surg17(2): 345–352. |
| 5646 | Singh, P. P. and S. Singh (2013). "Statins are associated with reduced risk of gastric cancer: a systematic review and meta-analysis." Ann Oncol24(7): 1721–1730. |
| 5652 | Singh, S., S. K. Garg, et al. (2013). "Acid-suppressive medications and risk of oesophageal adenocarcinoma in patients with Barrett's oesophagus: a systematic review and meta-analysis." Gut. |
| 5662 | Singh, S., A. G. Singh, et al. (2013). "Statins are associated with reduced risk of esophageal cancer, particularly in patients with Barrett's esophagus: a systematic review and meta-analysis." Clin Gastroenterol Hepatol11(6): 620–629. |
| 5674 | Singh, S., P. P. Singh, et al. (2013). "Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis." Gastroenterology144(2): 323–332. |
| 5768 | Song, Y., H. Nie, et al. (2013). "Association of statin use with risk of dementia: a meta-analysis of prospective cohort studies." Geriatr Gerontol Int13(4): 817–824. |
| 5902 | Sun, A., R. Liu, et al. (2013). "Insulin therapy and risk of colorectal cancer: an updated meta-analysis of epidemiological studies." Curr Med Res Opin. |
| 5912 | Sun, K., J. M. Liu, et al. (2013). "Bisphosphonate treatment and risk of esophageal cancer: a meta-analysis of observational studies." Osteoporos Int24(1): 279–286. |
| 6126 | Tleyjeh, I. M., A. B. Abdulhak, et al. (2013). "The association between histamine 2 receptor antagonist use and Clostridium difficile infection: a systematic review and meta-analysis." PLoS One8(3): e56498. |
| 6148 | Toulis, K. A., K. Hemming, et al. (2014). "beta-adrenergic receptor antagonists and fracture risk: a meta-analysis of selectivity, gender, and site-specific effects." Osteoporos Int25(1): 121–129. |
| 6194 | Tsakok, T., T. M. McKeever, et al. (2013). "Does early life exposure to antibiotics increase the risk of eczema? A systematic review." Br J Dermatol169(5): 983–991. |
| 6196 | Tsang, S. T. and P. Gaston (2013). "Adverse peri-operative outcomes following elective total hip replacement in diabetes mellitus: a systematic review and meta-analysis of cohort studies." Bone Joint J95-B(11): 1474–1479. |
| 6245 | Undela, K., K. Gudala, et al. (2013). "Statin use and risk of Parkinson's disease: a meta-analysis of observational studies." J Neurol260(1): 158–165. |
| 6363 | Varas-Lorenzo, C., N. Riera-Guardia, et al. (2013). "Myocardial infarction and individual nonsteroidal anti-inflammatory drugs meta-analysis of observational studies." Pharmacoepidemiol Drug Saf22(6): 559–570. |
| 6427 | Vis, M. M., M. A. Beijk, et al. (2013). "A systematic review and meta-analysis on primary percutaneous coronary intervention of an unprotected left main coronary artery culprit lesion in the setting of acute myocardial infarction." JACC Cardiovasc Interv6(4): 317–324. |
| 6524 | Wang, L., S. Cai, et al. (2013). "Insulin therapy contributes to the increased risk of colorectal cancer in diabetes patients: a meta-analysis." Diagn Pathol8(1): 180. |
| 6587 | Wang, Z. M., D. Zhao, et al. (2013). "Flavonol intake and the risk for stroke: A meta-analysis of cohort studies." Nutrition. |
| 6761 | Wu, Q., W. Qu, et al. (2013). "Tricyclic antidepressant use and risk of fractures: a meta-analysis of cohort and case–control studies." J Bone Miner Res28(4): 753–763. |
| 6777 | Wu, X. D., K. Zeng, et al. (2013). "Statins are associated with reduced risk of gastric cancer: a meta-analysis." Eur J Clin Pharmacol69(10): 1855–1860. |
| 6801 | Xie, Q., M. L. Chen, et al. (2013). "Isoflavone consumption and risk of breast cancer: a dose–response meta-analysis of observational studies." Asia Pac J Clin Nutr22(1): 118–127. |
| 6817 | Xing, D., X. L. Ma, et al. (2014). "Association between use of benzodiazepines and risk of fractures: a meta-analysis." Osteoporos Int25(1): 105–120. |
| 99 | Ahn, J. S., C. S. Eom, et al. (2013). "Acid suppressive drugs and gastric cancer: a meta-analysis of observational studies." World J Gastroenterol19(16): 2560–2568. |
| 1479 | Deshpande, A., V. Pasupuleti, et al. (2013). "Acid-suppressive therapy is associated with spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis." J Gastroenterol Hepatol28(2): 235–242. |
| 1567 | Dong, J. Y., W. G. Zhang, et al. (2013). "Vitamin D intake and risk of type 1 diabetes: a meta-analysis of observational studies." Nutrients5(9): 3551–3562. |
| 2881 | Jin, G., Z. Lanlan, et al. (2014). "Pregnancy outcome following loop electrosurgical excision procedure (LEEP) a systematic review and meta-analysis." Arch Gynecol Obstet289(1): 85–99. |
| 6972 | Yuhara, H., D. A. Corley, et al. (2013). "Aspirin and non-aspirin NSAIDs increase risk of colonic diverticular bleeding: a systematic review and meta-analysis." J Gastroenterol. |
| 3105 | Khan, M. F., C. S. Wendel, et al. (2013). "Effects of percutaneous revascularization of chronic total occlusions on clinical outcomes: a meta-analysis comparing successful versus failed percutaneous intervention for chronic total occlusion." Catheter Cardiovasc Interv82(1): 95–107. |
| 2357 | Haider, B. A., I. Olofin, et al. (2013). "Anaemia, prenatal iron use, and risk of adverse pregnancy outcomes: systematic review and meta-analysis." BMJ346: f3443. |
| 1865 | Filion, K. B., D. Chateau, et al. (2013). "Proton pump inhibitors and the risk of hospitalisation for community-acquired pneumonia: replicated cohort studies with meta-analysis." Gut. |
| Reason for exclusion: | |
| There is no comparison group (n = 22) | |
| Study ID | Reference of included citation |
| 239 | Andrews, P. L., J. R. Shiber, et al. (2013). "Early application of airway pressure release ventilation may reduce mortality in high-risk trauma patients: a systematic review of observational trauma ARDS literature." J Trauma Acute Care Surg75(4): 635–641. |
| 2186 | Gomberawalla, M. M., B. S. Miller, et al. (2013). "Meta-analysis of joint preservation versus arthroplasty for the treatment of displaced 3- and 4-part fractures of the proximal humerus." Injury44(11): 1532–1539. |
| 2214 | Gopal, M., N. Padayatchi, et al. (2013). "Systematic review of clofazimine for the treatment of drug-resistant tuberculosis." Int J Tuberc Lung Dis17(8): 1001–1007. |
| 2749 | Iftikhar, I. H., E. R. Hays, et al. (2013). "Effect of oral appliances on blood pressure in obstructive sleep apnea: a systematic review and meta-analysis." J Clin Sleep Med9(2): 165–174. |
| 3242 | Koy, A., M. Hellmich, et al. (2013). "Effects of deep brain stimulation in dyskinetic cerebral palsy: a meta-analysis." Mov Disord28(5): 647–654. |
| 3748 | Lopez-Olivo, M. A., G. Pratt, et al. (2013). "Rasburicase in tumor lysis syndrome of the adult: a systematic review and meta-analysis." Am J Kidney Dis62(3): 481–492. |
| 4255 | Moulakakis, K. G., S. N. Mylonas, et al. (2013). "A systematic review and meta-analysis of hybrid aortic arch replacement." Ann Cardiothorac Surg2(3): 247–260. |
| 4869 | Pirie, D. A., B. H. Wattar, et al. (2014). "Effects of monitoring strategies on seizures in pregnant women on lamotrigine: a meta-analysis." Eur J Obstet Gynecol Reprod Biol172: 26–31. |
| 5866 | Stone, J. C., J. Clark, et al. (2013). "Estrogen and selective estrogen receptor modulators (SERMs) for the treatment of acromegaly: a meta-analysis of published observational studies." Pituitary. |
| 998 | Chang, S. J., M. Hodeib, et al. (2013). "Survival impact of complete cytoreduction to no gross residual disease for advanced-stage ovarian cancer: a meta-analysis." Gynecol Oncol130(3): 493–498. |
| 3796 | Luksic, I., S. Clay, et al. (2013). "Effectiveness of seasonal influenza vaccines in children -- a systematic review and meta-analysis." Croat Med J54(2): 135–145. |
| 5836 | Stegeman, B. H., M. de Bastos, et al. (2013). "Different combined oral contraceptives and the risk of venous thrombosis: systematic review and network meta-analysis." BMJ347: f5298. |
| 6128 | Toczek, A., H. Cox, et al. (2013). "Strategies for reducing treatment default in drug-resistant tuberculosis: systematic review and meta-analysis." Int J Tuberc Lung Dis17(3): 299–307. |
| 1681 | El-Jurdi, N., T. Reljic, et al. (2013). "Efficacy of adoptive immunotherapy with donor lymphocyte infusion in relapsed lymphoid malignancies." Immunotherapy5(5): 457–466. |
| 4169 | Moawad, F. J., J. G. Cheatham, et al. (2013). "Meta-analysis: the safety and efficacy of dilation in eosinophilic oesophagitis." Aliment Pharmacol Ther38(7): 713–720. |
| 5546 | Sharma, S., C. Wu, et al. (2013). "Prevalence of complications in neuromuscular scoliosis surgery: a literature meta-analysis from the past 15 years." Eur Spine J22(6): 1230–1249. |
| 6104 | Tian, D. H., B. Wan, et al. (2013). "A systematic review and meta-analysis on the safety and efficacy of the frozen elephant trunk technique in aortic arch surgery." Ann Cardiothorac Surg2(5): 581–591. |
| 449 | Barrachina-Diez, J. M., E. Tashkandi, et al. (2013). "Long-term Outcome of One-Piece Implants. Part II: Prosthetic Outcomes. A Systematic Literature Review with Meta-Analysis." Int J Oral Maxillofac Implants28(6): 1470–1482. |
| 2587 | Hollingsworth, J. M., M. A. Rogers, et al. (2013). "Determining the noninfectious complications of indwelling urethral catheters: a systematic review and meta-analysis." Ann Intern Med159(6): 401–410. |
| 2787 | Iudici, M., S. Fasano, et al. (2013). "Prevalence and factors associated with glucocorticoids (GC) use in systemic sclerosis (SSc): a systematic review and meta-analysis of cohort studies and registries." Clin Rheumatol.i |
| 4562 | Orman, E. S., N. Li, et al. (2013). "Efficacy and durability of radiofrequency ablation for Barrett's Esophagus: systematic review and meta-analysis." Clin Gastroenterol Hepatol11(10): 1245–1255. |
| 5702 | Slater, N. J., M. van der Kolk, et al. (2013). "Biologic grafts for ventral hernia repair: a systematic review." Am J Surg205(2): 220–230. |
| Reason for exclusion: | |
| Not a meta-analysis/No statistical pooling of the results (n = 16) | |
| Study ID | Reference of included citation |
| 175 | Almekhlafi, M. A., B. K. Menon, et al. (2013). "A meta-analysis of observational intra-arterial stroke therapy studies using the Merci device, Penumbra system, and retrievable stents." AJNR Am J Neuroradiol34(1): 140–145. |
| 1103 | Chiappini, E., L. Galli, et al. (2013). "Use of combination neonatal prophylaxis for the prevention of mother-to-child transmission of HIV infection in European high-risk infants." AIDS27(6): 991–1000. |
| 1505 | Dienstknecht, T., K. Horst, et al. (2013). "A meta-analysis of operative versus nonoperative treatment in 463 scapular neck fractures." Scand J Surg102(2): 69–76. |
| 2431 | Hasan, S., L. Liu, et al. (2013). "The role of postoperative radiation and chemoradiation in merkel cell carcinoma: a systematic review of the literature." Front Oncol3: 276. |
| 1641 | Eckert, S., S. B. Freytag, et al. (2013). "Meta-analysis of three observational studies of amlodipine/valsartan in hypertensive patients with additional risk factors." Blood Press22 Suppl 1: 11–21. |
| 960 | Chacko, J., L. Harling, et al. (2013). "Can statins improve outcomes after isolated cardiac valve surgery? A systematic literature review." Clin Cardiol36(8): 448–455. |
| 3376 | Lane, D. A., S. Raichand, et al. (2013). "Combined anticoagulation and antiplatelet therapy for high-risk patients with atrial fibrillation: a systematic review." Health Technol Assess17(30): 1–188. |
| 1926 | Forman-Hoffman, V. L., A. J. Zolotor, et al. (2013). "Comparative effectiveness of interventions for children exposed to nonrelational traumatic events." Pediatrics131(3): 526–539. |
| 141 | Alcoba, G., M. Kerac, et al. (2013). "Do children with uncomplicated severe acute malnutrition need antibiotics? A systematic review and meta-analysis." PLoS One8(1): e53184. |
| 2763 | Ingargiola, M. J., L. N. Daniali, et al. (2013). "Does the application of incisional negative pressure therapy to high-risk wounds prevent surgical site complications? A systematic review." Eplasty13: e49. |
| 3250 | Krag, M., A. Perner, et al. (2013). "Stress ulcer prophylaxis in the intensive care unit: is it indicated? A topical systematic review." Acta Anaesthesiol Scand57(7): 835–847. |
| 4889 | Polk, A., M. Vaage-Nilsen, et al. (2013). "Cardiotoxicity in cancer patients treated with 5-fluorouracil or capecitabine: a systematic review of incidence, manifestations and predisposing factors." Cancer Treat Rev39(8): 974–984. |
| 4941 | Proietti, R., G. M. Manzoni, et al. (2013). "Can Cardiac Resynchronization Therapy Improve Cognitive Function? A Systematic Review." Pacing Clin Electrophysiol. |
| 1013 | Chapelle, C., S. Quenet, et al. (2013). "Antipsychotics: a real or confounding risk factor for venous thromboembolism?" Pharmacopsychiatry46(1): 36–37. |
| 1395 | de Tayrac, R. and L. Sentilhes (2013). "Complications of pelvic organ prolapse surgery and methods of prevention." Int Urogynecol J24(11): 1859–1872. |
| 1559 | Domecq, J. P., G. Prutsky, et al. (2013). "Adverse effects of the common treatments for polycystic ovary syndrome: a systematic review and meta-analysis." J Clin Endocrinol Metab98(12): 4646–4654. |
| Reason for exclusion: | |
| Meta-Analysis does not include results from observational studies (n = 12) | |
| Study ID | Reference of included citation |
| 87 | Ahmed, F., M. C. Lindley, et al. (2014). "Effect of influenza vaccination of healthcare personnel on morbidity and mortality among patients: systematic review and grading of evidence." Clin Infect Dis58(1): 50–57. |
| 125 | Albanna, A. S., B. M. Smith, et al. (2013). "Fixed-dose combination antituberculosis therapy: a systematic review and meta-analysis." Eur Respir J42(3): 721–732. |
| 1982 | Fu, R., S. Selph, et al. (2013). "Effectiveness and harms of recombinant human bone morphogenetic protein-2 in spine fusion: a systematic review and meta-analysis." Ann Intern Med158(12): 890–902. |
| 3004 | Kansagara, D., E. Dyer, et al. (2013). "Treatment of anemia in patients with heart disease: a systematic review." Ann Intern Med159(11): 746–757. |
| 2525 | Henson, C. C., S. Burden, et al. (2013). "Nutritional interventions for reducing gastrointestinal toxicity in adults undergoing radical pelvic radiotherapy." Cochrane Database Syst Rev11: CD009896. |
| 6034 | Taylor, P. N., O. E. Okosieme, et al. (2014). "Therapy of Endocrine Disease: Impact of iodine supplementation in mild-to-moderate iodine deficiency: systematic review and meta-analysis." Eur J Endocrinol170(1): R1-R15. |
| 753 | Bredemeier, M., F. K. de Oliveira, et al. (2013). "Low- versus high-dose rituximab for rheumatoid arthritis: A systematic review and meta-analysis." Arthritis Care Res (Hoboken). |
| 1791 | Fandino, M., K. I. Macdonald, et al. (2013). "The use of postoperative topical corticosteroids in chronic rhinosinusitis with nasal polyps: a systematic review and meta-analysis." Am J Rhinol Allergy27(5): e146-157. |
| 3316 | Kwok, C. S., V. Jeevanantham, et al. (2013). "No consistent evidence of differential cardiovascular risk amongst proton-pump inhibitors when used with clopidogrel: meta-analysis." Int J Cardiol167(3): 965–974. |
| 3012 | Kapadia, S., S. Hapani, et al. (2013). "Risk of liver toxicity with the angiogenesis inhibitor pazopanib in cancer patients." Acta Oncol52(6): 1202–1212. |
| 5089 | Reichenpfader, U., G. Gartlehner, et al. (2013). "Sexual Dysfunction associated with Second-Generation Antidepressants in Patients with Major Depressive Disorder: Results from a Systematic Review with Network Meta-Analysis." Drug Saf. |
| 1936 | Fortmann, S. P., B. U. Burda, et al. (2013). "Vitamin and Mineral Supplements in the Primary Prevention of Cardiovascular Disease and Cancer: An Updated Systematic Evidence Review for the U.S. Preventive Services Task Force." Ann Intern Med. |
| Reason for exclusion: | |
| Full text not available (n = 10) | |
| Study ID | Reference of included citation |
| 3702 | Liu, Y., P. Su, et al. (2013). "Endoscopic sphincterotomy plus balloon dilation versus endoscopic sphincterotomy for choledocholithiasis: A meta-analysis." J Gastroenterol Hepatol28(6): 937–945. |
| 3704 | Liu, Y., W. Tang, et al. (2013). "Association between statin use and colorectal cancer risk: a meta-analysis of 42 studies." Cancer Causes Control. |
| 4701 | Pasipanodya, J. G. and T. Gumbo (2013). "A meta-analysis of self-administered vs directly observed therapy effect on microbiologic failure, relapse, and acquired drug resistance in tuberculosis patients." Clin Infect Dis57(1): 21–31. |
| 5285 | Saheb, K. J., B. Q. Deng, et al. (2013). "Triple antithrombotic therapy versus double antiplatelet therapy after percutaneous coronary intervention with stent implantation in patients requiring chronic oral anticoagulation: a meta-analysis." Chin Med J (Engl)126(13): 2536–2542. |
| 5922 | Sun, Z. J., W. J. Li, et al. (2013). "Comparing minimally invasive and open transforaminal lumbar interbody fusion for treatment of degenerative lumbar disease: a meta-analysis." Chin Med J (Engl)126(20): 3962–3971. |
| 6783 | Wu, Y. C., J. F. Zhang, et al. (2013). "Transcatheter aortic valve implantation versus surgical aortic valve replacement for severe aortic stenosis: a meta analysis." Chin Med J (Engl)126(6): 1171–1177. |
| 7106 | Zheng, Z., L. Sheng, et al. (2013). "Statins and amyotrophic lateral sclerosis: a systematic review and meta-analysis." Amyotroph Lateral Scler Frontotemporal Degener14(4): 241–245. |
| 3598 | Lin, G. H., H. L. Chan, et al. (2013). "The Effect of Flapless Surgery on Implant Survival and Marginal Bone Level: A Systematic Review and Meta-analysis." J Periodontol. |
| 4225 | More, K., G. Athalye-Jape, et al. (2013). "Association of inhibitors of gastric acid secretion and higher incidence of necrotizing enterocolitis in preterm very low-birth-weight infants." Am J Perinatol30(10): 849–856. |
| 4175 | Moen, C. A., A. Burrell, et al. (2013). "Does tranexamic acid stop haemoptysis?" Interact Cardiovasc Thorac Surg17(6): 991–994. |
| Reason for exclusion: | |
| Meta-analysis not main objective (n = 6) | |
| Study ID | Reference of included citation |
| 1469 | D'Errigo, P., F. Biancari, et al. (2013). "Thirty-day mortality after coronary artery bypass surgery in patients aged <50 years: results of a multicenter study and meta-analysis of the literature." J Card Surg28(3): 207–211. |
| 1735 | Etminan, M., S. T. Bird, et al. (2013). "Isotretinoin and risk for inflammatory bowel disease: a nested case–control study and meta-analysis of published and unpublished data." JAMA Dermatol149(2): 216–220. |
| 1753 | Faggioli, G., R. Pini, et al. (2013). "Contralateral carotid occlusion in endovascular and surgical carotid revascularization: a single centre experience with literature review and meta-analysis." Eur J Vasc Endovasc Surg46(1): 10–20. |
| 3067 | Kennedy, N. A., E. Rhatigan, et al. (2013). "A trial of mercaptopurine is a safe strategy in patients with inflammatory bowel disease intolerant to azathioprine: an observational study, systematic review and meta-analysis." Aliment Pharmacol Ther38(10): 1255–1266. |
| 3624 | Linehan, M. F., U. Nurmatov, et al. (2013). "Does BCG vaccination protect against childhood asthma? Final results from the Manchester Community Asthma Study retrospective cohort study and updated systematic review and meta-analysis." J Allergy Clin Immunol. |
| 4455 | Nouri, K., M. Demmel, et al. (2013). "Prospective cohort study and meta-analysis of cyclic bleeding after laparoscopic supracervical hysterectomy." Int J Gynaecol Obstet122(2): 124–127. |
| Reason for exclusion: | |
| No observational studies (n = 4) | |
| Study ID | Reference of included citation |
| 946 | Cates, C. J. and B. H. Rowe (2013). "Vaccines for preventing influenza in people with asthma." Cochrane Database Syst Rev2: CD000364. |
| 2240 | Gouya, G., J. Arrich, et al. (2013). "Antiplatelet Treatment for Prevention of Cerebrovascular Events in Patients With Vascular Diseases: A Systematic Review and Meta-Analysis." Stroke. |
| 6484 | Wang, C. H., C. H. Huang, et al. (2013). "Biphasic versus monophasic defibrillation in out-of-hospital cardiac arrest: a systematic review and meta-analysis." Am J Emerg Med31(10): 1472–1478. |
| 4859 | Pineda, A. M., F. O. Nascimento, et al. (2013). "A meta-analysis of transcatheter closure of patent foramen ovale versus medical therapy for prevention of recurrent thromboembolic events in patients with cryptogenic cerebrovascular events." Catheter Cardiovasc Interv. |
| Reason for exclusion: | |
| Not published in 2013 (n = 4) | |
| Study ID | Reference of included citation |
| 179 | Almenawer, S. A., F. Farrokhyar, et al. (2013). "Chronic Subdural Hematoma Management: A Systematic Review and Meta-analysis of 34829 Patients." Ann Surg. |
| 3159 | Klatte, T., S. F. Shariat, et al. (2013). "Systematic review and meta-analysis of perioperative and oncological outcomes of laparoscopic cryoablation versus laparoscopic partial nephrectomy for the treatment of small renal tumors." J Urol. |
| 5708 | Sligl, W. I., L. Asadi, et al. (2013). "Macrolides and Mortality in Critically Ill Patients With Community-Acquired Pneumonia: A Systematic Review and Meta-Analysis." Crit Care Med. |
| 6482 | Wang, C. H., W. H. Hsieh, et al. (2013). "Liberal Versus Restricted Fluid Resuscitation Strategies in Trauma Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials and Observational Studies." Crit Care Med. |
| Reason for exclusion: | |
| Individual Patient Data meta-analysis (n = 2) | |
| Study ID | Reference of included citation |
| 5616 | Simmonds, M. C., J. V. Brown, et al. (2013). "Safety and effectiveness of recombinant human bone morphogenetic protein-2 for spinal fusion: a meta-analysis of individual-participant data." Ann Intern Med158(12): 877–889. |
| 485 | Bazelier, M. T., F. de Vries, et al. (2013). "Risk of fracture with thiazolidinediones: an individual patient data meta-analysis." Front Endocrinol (Lausanne)4: 11. |
Footnotes
Competing interests
The authors declare that they have no competing interests.
Authors’ contribution
TF was involved in the study conception, study selection, data extraction, interpretation of results, and drafting the manuscript.
PR was involved in the study conception, interpretation of the results, and drafting the manuscript. CR was involved in data extraction. EP was involved in data analysis. AD was involved in the study conception, interpretation of the results, and drafting the manuscript. All authors read and approved the final manuscript.
Contributor Information
Timor Faber, Email: timorfaber@gmail.com.
Philippe Ravaud, Email: philipperavaud@gmail.com.
Carolina Riveros, Email: carolina.riveros@aphp.fr.
Elodie Perrodeau, Email: elodie.perrodeau@gmail.com.
Agnes Dechartres, Email: agnes.dechartres@aphp.fr, Email: agnes.dechartres@htd.aphp.fr.
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