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A GRADE Working Group approach for rating the quality of treatment effect estimates from network meta-analysis
Open accessAbstract
Network meta-analysis (NMA), combining direct and indirect comparisons, is increasingly being used to examine the comparative effectiveness of medical interventions. Minimal guidance exists on how to rate the quality of evidence supporting treatment effect estimates obtained from NMA. We present a four-step approach to rate the quality of evidence in each of the direct, indirect, and NMA estimates based on methods developed by the GRADE working group. Using an example of a published NMA, we show that the quality of evidence supporting NMA estimates varies from high to very low across comparisons, and that quality ratings given to a whole network are uninformative and likely to mislead.
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“The overall certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework [45].”
From The Effect of Different Psychological Interventions on Athletes' Competitive Anxiety: A Systematic Review and Bayesian Network Meta-Analysis. (2026) · cites this paper as [45]
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“Therefore, we downgraded the quality of evidence for the comparison between SGLT2i and finerenone, SGLT2i and GLP-1 RA.”
In the citing paper
“Network meta-analysis, rather than pairwise meta-analysis, provides useful information about the comparative effectiveness of treatments that have not been tested head to head.”
From Drug treatments for covid-19: living systematic review and network meta-analysis (2020) · cites this paper as [5]
In the citing paper
“Moreover, the incorporation of indirect evidence can strengthen evidence in comparisons that were tested head to head.5”
From Drug treatments for covid-19: living systematic review and network meta-analysis (2020) · cites this paper as [5]
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Self-citationGRADE guidelines 6. Rating the quality of evidence—imprecision
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“, has a large confidence interval) or consistency (includes studies with conflicting results and a high unexplained heterogeneity), or are indirect (not directly related to the population in questions) (Puhan et al., 2014).”
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Dost, B., CASSAI, A. D., Bugada, D., Balzani, E., Karapınar, Y. E., Beldağlı, M., Yalin, M. S. O., Tulgar, S., & Ahişkalıoğlu, A. (2025) · Minerva Anestesiologica · doi:10.23736/s0375-9393.25.18771-3 · Cited by 9
Bajaj, N. S., Kalra, R., Patel, N., Hashim, T., Godara, H., Ather, S., Arora, G., Pasala, T. K. R., Whitfield, T. T., McGiffin, D. C., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0163608 · Cited by 10
“The GRADE guidelines were used to assess the quality of direct and indirect comparisons [23].”
MethodVeettil, S. K., Kew, S. T., Lim, K. G., Phisalprapa, P., Kumar, S., V, Lee, Y. Y., & Chaiyakunapruk, N. (2021) · BMC Gastroenterology · doi:10.1186/s12876-021-01715-7 · Cited by 9
“Assessment, Development and Evaluation (GRADE) approach [23].”
Mishra, S. K., Garg, K., Gaonkar, V. B., Singh, P. M., Singh, M., Suri, A., Chandra, P. S., & Kale, S. S. (2021) · World Neurosurgery · doi:10.1016/j.wneu.2021.07.104 · Cited by 9
Martín, Zhou, Y., Takagi, T., & Tian, Y. (2022) · International Journal of Clinical Pharmacy · doi:10.1007/s11096-022-01410-x · Cited by 9
“According to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE), the confidence rating of the evidence could be classified as “high,” “moderate,” “low,” and “very low” [22].”
MethodNovak‐Pavlic, M., Rosenbaum, P., Macedo, L. G., Rezze, B. D., Yong, J., Noori, A., & Hughes, D. (2022) · JMIR Research Protocols · doi:10.2196/38686 · Cited by 9
“We will first rate the importance of relevant outcomes in the literature as either critical, important but not critical, or of limited importance [32].”
BackgroundZhou, Z., Xu, G., Huang, L., Shu, Y., Tian, H., Huang, F., Liu, Y., Liang, F., & Sun, M. (2022) · Journal of Pain Research · doi:10.2147/jpr.s387756 · Cited by 9
Liao, G., Wang, X., Li, Y., Chen, X., Huang, K., Bai, L., Ye, Y., & Peng, Y. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics15010006 · Cited by 10
“Then, we used the GRADE approach for entire networks, providing the framework for rating the certainty of the evidence of each paired comparison as high, moderate, low, or very low [11,12].”
Guo, X., Zhou, Y., Zhang, K., Lü, W., Zhong, X. Z., Wu, S., Shen, L., Chen, H., & Chen, Y. (2023) · Journal of Evidence-Based Medicine · doi:10.1111/jebm.12571 · Cited by 10
The effect of intermittent theta burst stimulation for cognitive dysfunction: a meta-analysis
Zheng, B., Chen, J., Cao, M., Zhang, Y., Chen, S., Yu, H., & Liang, K. (2024) · Brain Injury · doi:10.1080/02699052.2024.2344087 · Cited by 9
“The quality of evidence was evaluated using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach (40).”
MethodKobleder, A., Raphaelis, S., Glaus, A., Fliedner, M., Mueller, M. D., Gafner, D., Gehrig, L., & Senn, B. (2016) · European Journal of Oncology Nursing · doi:10.1016/j.ejon.2016.10.003 · Cited by 9
Mitra, S., Disher, T. C., Pichler, G., D’Souza, B., McCord, H., Chayapathi, V., Jones, K., & Schmölzer, G. M. (2019) · BMJ Open · doi:10.1136/bmjopen-2018-028066 · Cited by 9
“For this purpose, the GRADE approach recommends to assess the incoherence (or inconsistency as described in the ‘Network Meta-Analysis’ section) criteria, which is defined as the differences between direct and indirect estimates of effect.(59)”
MethodSurgical interventions for treating intracapsular hip fractures in adults: a network meta-analysis
Sreekanta, A., Eardley, W. G., Wood, H., Glanville, J., Cook, J. A., & Griffin, X. L. (2019) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd013404 · Cited by 10
Wang, R., Wang, J., Shu, J., Gu, X., Li, H., Zi, Y., Liu, S., & Lin, J. (2020) · Medicine · doi:10.1097/md.0000000000018551 · Cited by 9
“GRADE pro software from Cochrane Systematic Reviews will be applied to create a Summary of Findings table.([27])”
Methodde Zoete, R. M. J., McAuley, J. H., Armfield, N. R., & Sterling, M. M. (2020) · BMJ Open · doi:10.1136/bmjopen-2019-034846 · Cited by 9
Effect of statins on cardiovascular complications in chronic kidney disease patients
Hwang, S. D., Kim, K., Kim, Y. J., Lee, S. W., Lee, J. H., & Song, J. H. (2020) · Medicine · doi:10.1097/md.0000000000020061 · Cited by 9
“Assessment, Development, and Evaluation (GRADE) approach.([12]) The quality of the evidence for a specific outcome was based on the performance versus the limitations of the study design, inconsistency of results, indirectness of evidence, imprecision of results, and publication bias among all studies measuring a part…”
BackgroundTorbahn, G., Schoene, D., Schwingshackl, L., Rücker, G., Knüttel, H., KEMMLER, W. K., Sieber, C. C., Batsis, J. A., Villareal, D. T., Stroebele‐Benschop, N., et al. (2020) · BMJ Open · doi:10.1136/bmjopen-2020-038330 · Cited by 9
Rao, L., Liu, X., Yu, L., & Xiao, H. (2021) · Medicine · doi:10.1097/md.0000000000024776 · Cited by 9
“We will use the Grading of Recommendation Assessment, Development and Evaluation scoring method to grade the evidence of the outcome index.([16]) The evaluation content includes bias risk, indirectness, inconsistency, inaccuracy and publication bias, and the quality of evidence will be rated as high, medium, low or ve…”
MethodEffectiveness and safety of massage for athletic injuries
Guo, G., Xie, S., Cai, F., Zhou, X., Xu, J., Wu, B., Wu, G., Xiao, R., Xu, X., Lu, P., et al. (2021) · Medicine · doi:10.1097/md.0000000000026925 · Cited by 9
“quality.([25]) In addition, we will use the online guideline development tool to conduct this process.”
MethodSaid, S. A., Alabed, S., Kaier, K., Bode, C., Meerpohl, J. J., & Duerschmied, D. (2019) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd013252 · Cited by 9
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Pathak, M., Deo, S. V. S., Dwivedi, S. N., Thakur, B., Sreenivas, V., & Rath, G. K. (2020) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2020.103015 · Cited by 9
Wen, L., Huang, B., Tu, R., Wan, K., Zhang, H., & Zhang, X. (2021) · BMJ Open · doi:10.1136/bmjopen-2020-043585 · Cited by 9
Ibrahim, A. A. E., McWilliams, D. F., Smith, S. L., Chaplin, W. J., Salimian, M., Georgopoulos, V., Kouraki, A., & Walsh, D. A. (2025) · Annals of Physical and Rehabilitation Medicine · doi:10.1016/j.rehab.2024.101894 · Cited by 9
Nutritional supplementation for nonalcohol-related fatty liver disease: a network meta-analysis
Komolafe, O., Buzzetti, E., Linden, A., Best, L. M., Madden, A. M., Roberts, D., Chase, T. J., Fritche, D., Freeman, S. C., Cooper, N. J., et al. (2021) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd013157.pub2 · Cited by 21
Sehmbi, H., Retter, S., Shah, U. J., Nguyen, D. L., Martin, J. E., & Uppal, V. (2023) · Canadian Journal of Anesthesia/Journal canadien d anesthésie · doi:10.1007/s12630-023-02510-6 · Cited by 7
“Despite this, further considerations are needed for the protocol,(7) graphical presentation of results,(8) and assessment of certainty.(9) The PRISMA Extension Statement for Reporting of Systematic Reviews Incorporating Network Meta-analyses (PRISMA-NMA) of Health Care Interventions was introduced in June 2015.”
BackgroundYu, C., Zhang, R., Shen, B., Li, X., Fang, Y., Jiang, Y., & Jian, G. (2023) · Medicine · doi:10.1097/md.0000000000035275 · Cited by 8
“[66,67] The quality of the evidence for outcomes ranged from “low” to “moderate,” with the principal reasons for the degradation being imprecise meta-analysis results and the risk of bias (Supplementary Material S9, http://links.lww.com/MD/ K710 and S10, http://links.lww.com/MD/K711).”
BackgroundHusein‐ElAhmed, H., & Husein-ElAhmed, S. (2024) · Indian Journal of Dermatology Venereology and Leprology · doi:10.25259/ijdvl_665_2023 · Cited by 8
“47 To address interpretation challenges, it has been proposed that NMA authors complement numerical data with graphical and ranking tools, 48 bearing in mind that each tool has limitations and requires cautious interpretation.”
Metadata
- Authors
- Puhan, M. A., Schunemann, H. J., Murad, M. H., Li, T., Brignardello-Petersen, R., Singh, J. A., Kessels, A. G., Guyatt, G. H., & for the GRADE Working Group
- Affiliations
- University of Zurich (CH)
- Mayo Clinic (US)
- Johns Hopkins University (US)
- University of Alabama (US)
- Maastricht University (NL)
- McMaster University (CA)
- Corresponding author
- Puhan, M. A.
- Venue
- BMJ
- Publisher
- BMJ
- Published
- 2014-09-24
- Volume
- 349
- Issue
- sep24 5
- Pages
- g5630-g5630
- ISSN
- 1756-1833 (ISSN-L)
- OpenAlex
- W2155798268
- Cited by
- 1,812
- References
- 39
- Citations by year
- 2026: 160 · 2025: 177 · 2024: 216 · 2023: 175 · 2022: 205 · 2021: 276 · 2020: 201 · 2019: 128 · 2018: 96 · 2017: 72 · 2016: 63 · 2015: 36 · 2014: 4
- FWCI
- 57.15
- Type
- journal article
- Language
- en
- Update notices
- correction (2015-06-17)
- Open access
- bronze
- doi.org
- Locations
- BMJ (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- HighWire Press Open Archive (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich)
- Topics
- Social Sciences › Decision Sciences › Statistics, Probability and Uncertainty › Meta-analysis and systematic reviews
- Social Sciences › Sociology and Political Science › Delphi Technique in Research
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Clinical practice guidelines implementation
- Keywords
- network meta-analysis, quality of evidence, GRADE, treatment effect estimates, comparative effectiveness
- MeSH terms
- Humans, Quality Assurance, Health Care, Meta-Analysis as Topic, Practice Guidelines as Topic, Evidence-Based Medicine, Guideline Adherence
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