Quantitative Synthesis in Systematic Reviews
Abstract
The final common pathway for most systematic reviews is a statistical summary of the data, or meta-analysis. The complex methods used in meta-analyses should always be complemented by clinical acumen and common sense in designing the protocol of a systematic review, deciding which data can be combined, and determining whether data should be combined. Both continuous and binary data can be pooled. Most meta-analyses summarize data from randomized trials, but other applications, such as the evaluation of diagnostic test performance and observational studies, have also been developed. The statistical methods of meta-analysis aim at evaluating the diversity (heterogeneity) among the results of different studies, exploring and explaining observed heterogeneity, and estimating a common pooled effect with increased precision. Fixed-effects models assume that an intervention has a single true effect, whereas random-effects models assume that an effect may vary across studies. Meta-regression analyses, by using each study rather than each patient as a unit of observation, can help to evaluate the effect of individual variables on the magnitude of an observed effect and thus may sometimes explain why study results differ. It is also important to assess the robustness of conclusions through sensitivity analyses and a formal evaluation of potential sources of bias, including publication bias and the effect of the quality of the studies on the observed effect.
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Thirty-nine articles (42%) made recommendations on the assessment of quality and risk of bias of individual studies, with publication dates between 1994 and 2016 (median year 2009).
“Thirty-nine articles (42%) made recommendations on the assessment of quality and risk of bias of individual studies, [12, 16, 29, 30, 32–35, 37, 38, 43, 47–50, 52–54, 56, 64–66, 70, 71, 73, 75, 77, 82, 84–94] with publication dates between 1994 and 2016 (median year of publication 2009).”
From Methods to systematically review and meta-analyse observational studies: a systematic scoping review of recommendations (2018) · cites this paper as [16]
Twenty (22%) articles reported on item "publication bias", with publication dates between 1994 and 2012 (median year 2001).
“Twenty (22%) articles reported on item “publication bias” [16, 29, 33, 34, 36, 46, 48–50, 55, 56, 61, 70, 78, 85, 95–99], with publication dates between 1994 and 2012 (median year of publication 2001).”
From Methods to systematically review and meta-analyse observational studies: a systematic scoping review of recommendations (2018) · cites this paper as [16]
The need for complete reporting of all relevant methodological aspects as a prerequisite to assessing the risk of bias of studies was highlighted in 10 articles, and was the focus of recommendations in a publication from the MOOSE group.
“The need for complete reporting of all relevant methodological aspects as a prerequisite to assessing the risk of bias of studies was highlighted in 10 articles, [16, 33, 35, 47, 50, 56, 86, 87, 90, 91] and was the focus of recommendations in a publication from the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group [12].”
From Methods to systematically review and meta-analyse observational studies: a systematic scoping review of recommendations (2018) · cites this paper as [16]
Thirty-nine articles (42%) provided recommendations on heterogeneity and its assessment, with publication dates between 1994 and 2016 (median year 2006).
“Thirty-nine articles (42%) provided recommendations on heterogeneity and its assessment, [8, 12, 16, 29, 30, 33, 34, 36, 38, 39, 41–44, 47, 49–52, 54–56, 61, 66, 70, 72, 77, 82, 85, 87, 98, 100–107] with publication dates between 1994 and 2016 (median year of publication 2006).”
From Methods to systematically review and meta-analyse observational studies: a systematic scoping review of recommendations (2018) · cites this paper as [16]
Fifty-two articles (56%) provided recommendations on the statistical analysis in the context of meta-analysis of observational studies, with publication dates between 1994 and 2016 (median year 2006).
“Fifty-two articles (56%), provided recommendations on the statistical analysis in the context of meta-analysis of observational studies [8, 12, 16, 29–31, 33–36, 38, 41–44, 47, 48, 52, 54–56, 61, 66, 70, 72, 73, 77, 79–83, 85, 87, 96, 100, 101, 103–105, 107–118], with publication dates between 1994 and 2016 (median year of publication 2006).”
From Methods to systematically review and meta-analyse observational studies: a systematic scoping review of recommendations (2018) · cites this paper as [16]
One common recommendation was to explore heterogeneity in sensitivity analyses, comparing studies stratified by design or clinical features.
“One common recommendation was to explore heterogeneity in sensitivity analyses, comparing studies stratified by design or clinical features [12, 16, 29, 34, 39, 51, 55, 56, 66, 77, 85, 100, 102].”
From Methods to systematically review and meta-analyse observational studies: a systematic scoping review of recommendations (2018) · cites this paper as [16]
Different articles advise to graphically examine the presence of publication bias using funnel plots, or to assess it with statistical tests.
“Since “journals are typically more likely to publish results that establish a difference than those that do not” [48], and publication bias is difficult to eliminate, different articles advise to graphically examine its presence using funnel plots, or to assess it with statistical tests [16, 36, 48, 55, 85, 97, 99].”
From Methods to systematically review and meta-analyse observational studies: a systematic scoping review of recommendations (2018) · cites this paper as [16]
The use of a random-effects model for meta-analysis of observational studies by default was frequently recommended.
“Second, the use of a random-effects model for meta-analysis of observational studies by default was frequently recommended [8, 16, 29, 34, 70, 77, 100, 101].”
From Methods to systematically review and meta-analyse observational studies: a systematic scoping review of recommendations (2018) · cites this paper as [16]
A fixed-effect model using the method of Mantel and Haenszel was used when there was no significant heterogeneity, and a random effect model was used when heterogeneity was significant.
“We used a fixed‐effect model, using the method of Mantel and Haenszel when there was no significant heterogeneity, and a random effect model when heterogeneity was significant.34”
From Gut Microbiota Metabolites and Risk of Major Adverse Cardiovascular Disease Events and Death: A Systematic Review and Meta‐Analysis of Prospective Studies (2017) · cites this paper as [34]
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“(19), and quantify the relative benefits of lowmolecular-weight heparin treatment (20).”
BackgroundPrioritizing GWAS Results: A Review of Statistical Methods and Recommendations for Their Application
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“Inverse variance weights can be estimated under a fixed-effects model or under a random-effects model.(10,12) In general, fixed-effects models assume that all genetic variation between studies is due to random error, whereas random-effects models also allow variation due to real population differences such as ethnic a…”
BackgroundOptimally estimating the sample standard deviation from the five‐number summary
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“Note that the new estimator is a weighted combination of estimators (2) and (3).”
BackgroundMethodInfluentialPhysical activity and survival after breast cancer diagnosis: Meta-analysis of published studies
Ibrahim, E. M., & Al-Homaidh, A. (2011) · Medical Oncology · doi:10.1007/s12032-010-9536-x · Cited by 604 · see citing works
“1, the assumption of homogeneity was deemed invalid, and the random-effects model was reported after exploring the causes of heterogeneity [18].”
BackgroundImaging strategies for low-back pain: systematic review and meta-analysis
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A solution to minimum sample size for regressions
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The Association between Smoking and Low Back Pain: A Meta-analysis
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Genetic associations in large versus small studies: an empirical assessment
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Depression and the risk of coronary heart disease: a meta-analysis of prospective cohort studies
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“The RRs were pooled using the fixed-effects model if no heterogeneity was detected, or the random-effects model was used otherwise [19].”
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Injection allergen immunotherapy for asthma
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Kramer, D. G., Trikalinos, T. A., Kent, D. M., Antonopoulos, G. V., Konstam, M. A., & Udelson, J. E. (2010) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2010.05.011 · Cited by 495 · see citing works
“10) (31) and calculated its ext ent with I(2) (32).”
BackgroundTerrin, N. C., Schmid, C. H., & Lau, J. (2005) · Journal of Clinical Epidemiology · doi:10.1016/j.jclinepi.2005.01.006 · Cited by 493 · see citing works
“68–69 and [43]).”
Self-citationBalk, E. M. (2002) · JAMA · doi:10.1001/jama.287.22.2973 · Cited by 478 · see citing works
“10 for the 2 statistic or a nonzero between-study variance, (2), by the DerSimonian and Laird random-effects model).(35,36) We required statistical heterogeneity of treatment effect across trials within each meta-analysis because meta-analyses with homogenous treatment effects across trials are unlikely to find that e…”
BackgroundSpinal Manipulative Therapy for Low Back Pain
Assendelft, W. J., Morton, S. C., Yu, E. I., Suttorp, M. J., & Shekelle, P. (2003) · Annals of Internal Medicine · doi:10.7326/0003-4819-138-11-200306030-00008 · Cited by 476 · see citing works
“We incorporate relevant clinical variables and combine them with meta-analytic techniques to estimate the effectiveness of spinal manipulative therapy relative to other commonly used therapies (21).”
MethodUltrasound guidance versus anatomical landmarks for internal jugular vein catheterization
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Acetylcysteine for prevention of contrast nephropathy: meta-analysis
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Meta-Analyses of Therapies for Postmenopausal Osteoporosis
Osteoporosis Methodology Group (2002) · Endocrine Reviews · doi:10.1210/edrv.23.4.0486 · Cited by 471 · see citing works
Economou, M., Trikalinos, T. A., Loizou, K. T., Tsianos, E. V., & Ioannidis, J. P. A. (2004) · The American Journal of Gastroenterology · doi:10.1111/j.1572-0241.2004.40304.x · Cited by 464 · see citing works
“For each comparison, we estimated the between-study heterogeneity (statistical dissimilarity of the results) using the χ2-based Q statistic (23, 24).”
MethodSelf-citationKöhler, C. A., Freitas, T. H., Stubbs, B., Maes, M., Solmi, M., Veronese, N., de Andrade, N. Q., Morris, G., Fernandes, B. S., Brunoni, A. R., et al. (2017) · Molecular Neurobiology · doi:10.1007/s12035-017-0632-1 · Cited by 449 · see citing works
“Randomeffects modeling assumes a genuine diversity across studies and incorporates a between-study variance into the calculations [20].”
Murad, M. H., Montori, V. M., Ioannidis, J. P. A., Jaeschke, R., Devereaux, P. J., Prasad, K., Neumann, I., Carrasco-Labra, A., Agoritsas, T., Hatala, R., et al. (2014) · JAMA · doi:10.1001/jama.2014.5559 · Cited by 454 · see citing works
Self-citationGeleijnse, J. M., Kok, F. J., & Grobbee, D. E. (2003) · Journal of Human Hypertension · doi:10.1038/sj.jhh.1001575 · Cited by 446 · see citing works
Allergen immunotherapy for asthma
Abramson, M. J., Puy, R. M., & Weiner, J. M. (2003) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd001186 · Cited by 433 · see citing works
Hapani, S., Chu, D. T. W., & Wu, S. (2009) · The Lancet Oncology · doi:10.1016/s1470-2045(09)70112-3 · Cited by 431 · see citing works
Physical Activity Before and During Pregnancy and Risk of Gestational Diabetes Mellitus
Tobias, D. K., Zhang, C., van Dam, R. M., Bowers, K., & Hu, F. B. (2011) · Diabetes Care · doi:10.2337/dc10-1368 · Cited by 429 · see citing works
“Statistical analysis A random-effects meta-analysis was conducted to combine the relative risks reported for the original studies (15).”
MethodMueller, M., D’Addario, M., Egger, M., Cevallos, M., Dekkers, O., Mugglin, C., & Scott, P. (2018) · BMC Medical Research Methodology · doi:10.1186/s12874-018-0495-9 · Cited by 400 · see citing works
“Second, the use of a random-effects model for meta-analysis of observational studies by default was frequently recommended [8, 16, 29, 34, 70, 77, 100, 101].”
BackgroundMethodResultInfluentialEnvironmental risk factors and Parkinson's disease: An umbrella review of meta-analyses
Bellou, V., Belbasis, L., Tzoulaki, I., Εvangelou, Ε., & Ioannidis, J. P. A. (2015) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2015.12.008 · Cited by 429 · see citing works
“For each meta-analysis, we estimated the summary effect size and its 95% CI using both fixed-effects and random-effects models [9,10].”
Self-citationPercutaneous Coronary Intervention Versus Conservative Therapy in Nonacute Coronary Artery Disease
Katritsis, D. G., & Ioannidis, J. P. A. (2005) · Circulation · doi:10.1161/circulationaha.104.521864 · Cited by 427 · see citing works
Self-citationCharacterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor
Belum, V. R., Benhuri, B., Postow, M. A., Hellmann, M. D., Lesokhin, A. M., Segal, N. H., Motzer, R. J., Wu, S., Busam, K. J., Wolchok, J. D., et al. (2016) · European Journal of Cancer · doi:10.1016/j.ejca.2016.02.010 · Cited by 418 · see citing works
Myofunctional Therapy to Treat Obstructive Sleep Apnea: A Systematic Review and Meta-analysis
Camacho, M., Certal, V., Abdullatif, J. D., Zaghi, S., Ruoff, C. M., Capasso, R., & Kushida, C. A. (2015) · SLEEP · doi:10.5665/sleep.4652 · Cited by 420 · see citing works
Hoffman, S. N., Tenbrook, J., Wolf, M. P., Pauker, S., Salem, D., & Wong, J. (2003) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(03)00157-8 · Cited by 455 · see citing works
“CABG 61 (12) 30 (47) 0 (0) 39 (22) 77 (40) 222 (43) n/a 376 (41) 23 (30) n/a 130 (58) 200 (33) 236 (47)”
InfluentialScreen time and childhood overweight/obesity: A systematic review and meta‐analysis
Fang, K., Mu, M., Liu, K., & He, Y. (2019) · Child Care Health and Development · doi:10.1111/cch.12701 · Cited by 399 · see citing works
Follow-up of patients with curatively resected colorectal cancer: a practice guideline
Figueredo, A., Rumble, R. B., Maroun, J., Earle, C. C., Cummings, B., McLeod, R., Zuraw, L., Zwaal, C., & the members of the Gastrointestinal Cancer Disease Site Group of Cancer Care Ontario's Program in Evidence-based Care (2003) · BMC Cancer · doi:10.1186/1471-2407-3-26 · Cited by 392 · see citing works
“Inverted funnel plots were done to investigate publication bias [34].”
BackgroundShah, N. R., & Bracken, M. B. (2000) · American Journal of Obstetrics and Gynecology · doi:10.1016/s0002-9378(00)70240-7 · Cited by 394 · see citing works
“Studies selected for analysis had to meet the following requirements: (1) The study was prospective (ie, smoking exposure was ascertained before perinatal outcome); (2) the study reported data on rates of preterm delivery stratified across at least two levels of maternal smoking, or the study included a summary estima…”
MethodRoos, J. F., Doust, J. A., Tett, S. E., & Kirkpatrick, C. M. J. (2007) · Clinical Biochemistry · doi:10.1016/j.clinbiochem.2006.10.026 · Cited by 392 · see citing works
Prevalence and associated factors of antenatal depression: Systematic reviews and meta-analyses
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Meulendijks, D., Henricks, L. M., Sonke, G. S., Deenen, M. J., Froehlich, T. K., Amstutz, U., Largiadèr, C. R., Jennings, B. A., Marinaki, A. M., Sanderson, J. D., et al. (2015) · The Lancet Oncology · doi:10.1016/s1470-2045(15)00286-7 · Cited by 382 · see citing works
Ioannidis, J. P. A., Abrams, E. J., Ammann, A. J., Bulterys, M., Goedert, J. J., Gray, L., Korber, B., Mayaux, M. J., MOFENSON, L. M., Newell, M., et al. (2001) · The Journal of Infectious Diseases · doi:10.1086/318530 · Cited by 379 · see citing works
“Heterogeneity of the risk ratios was assessed by using the Q statistic [24].”
MethodSelf-citationShortened Telomere Length Is Associated with Increased Risk of Cancer: A Meta-Analysis
Ma, H., Zhou, Z., Wei, S., Liu, Z., Pooley, K. A., Dunning, A. M., Svenson, U., Roos, G., Hosgood, H. D., Shen, M., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0020466 · Cited by 376 · see citing works
“05 [45].”
Revisão sistemática: uma revisão narrativa
Cordeiro, A. M., de Oliveira, G. M., Rentería, J. M., & Guimarães, C. A. (2007) · Revista do Colégio Brasileiro de Cirurgiões · doi:10.1590/s0100-69912007000600012 · Cited by 373 · see citing works
Atieh, M. A., Ibrahim, H., & Atieh, A. H. (2010) · Journal of Periodontology · doi:10.1902/jop.2010.100232 · Cited by 375 · see citing works
Spinal manipulative therapy for low-back pain
Assendelft, W. J., Morton, S. C., Yu, E. I., Suttorp, M. J., & Shekelle, P. (2004) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd000447.pub2 · Cited by 368 · see citing works
RetractedRong, Y., Chen, L., Zhu, T., Song, Y., Yu, M., Shan, Z., Sands, A., Hu, F. B., & Liu, L. (2013) · BMJ · doi:10.1136/bmj.e8539 · Cited by 364 · see citing works
Failure rates and associated risk factors of orthodontic miniscrew implants: A meta-analysis
Papageorgiou, S. N., Zogakis, I. P., & Papadopoulos, M. A. A. P. (2012) · American Journal of Orthodontics and Dentofacial Orthopedics · doi:10.1016/j.ajodo.2012.05.016 · Cited by 366 · see citing works
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“10 was considered statistically significant for heterogeneity.(23) Degree of heterogeneity is reported according to the I(2) statistic, which refers to the degree of variation between studies.”
BackgroundAspirin for the Prevention of Cardiovascular Events in Patients With Peripheral Artery Disease
Berger, J. S., Krantz, M. J., Kittelson, J. M., & Hiatt, W. R. (2009) · JAMA · doi:10.1001/jama.2009.623 · Cited by 357 · see citing works
“The Cochran Q statistic and I(2) statistic were calculated to assess the degree of heterogeneity among the trials.(18) The Q statisticdidnot indicate statistically significant heterogeneity for any end point.”
MethodMaxillomandibular Advancement for Treatment of Obstructive Sleep Apnea: A Meta-analysis
Zaghi, S., Holty, J.-E. C., Certal, V., Abdullatif, J., Guilleminault, C., Powell, N. B., Riley, R. W., & Camacho, M. (2016) · JAMA Otolaryngology–Head & Neck Surgery · doi:10.1001/jamaoto.2015.2678 · Cited by 355 · see citing works
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Systematic reviews and meta-analyses: an illustrated, step-by-step guide.
Pai, M., McCulloch, M., Gorman, J. D., Pai, N. P., Enanoria, W. T. A., Kennedy, G., Tharyan, P., & Colford, J. M. (2004) · PubMed · Cited by 346 · see citing works
Kong, D. F., Califf, R. M., Miller, D. P., Moliterno, D. J., White, H. D., Harrington, R. A., Tcheng, J. E., Lincoff, A. M., Hasselblad, V., & Topol, E. J. (1998) · Circulation · doi:10.1161/01.cir.98.25.2829 · Cited by 346 · see citing works
Alonso, A., Lau, J., Jaber, B. L., Weintraub, A., & Sarnak, M. J. (2004) · American Journal of Kidney Diseases · doi:10.1053/j.ajkd.2003.09.009 · Cited by 345 · see citing works
Self-citationPrevalence and outcomes of incidental imaging findings: umbrella review
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Self-citationMeta-analysis of vascular and neoplastic events associated with tamoxifen
Braithwaite, R. S., Chlebowski, R. T., Lau, J., George, S., Hess, R., & Col, N. F. (2003) · Journal of General Internal Medicine · doi:10.1046/j.1525-1497.2003.20724.x · Cited by 337 · see citing works
Self-citationBalloon Kyphoplasty and Vertebroplasty for Vertebral Compression Fractures
Taylor, R. S., Taylor, R. J., & Fritzell, P. (2006) · Spine · doi:10.1097/01.brs.0000244639.71656.7d · Cited by 331 · see citing works
Advancing Maternal Age Is Associated With Increasing Risk for Autism: A Review and Meta-Analysis
Sandin, S., Hultman, C. M., Kolevzon, A. L., Gross, R., MacCabe, J. H., & Reichenberg, A. (2012) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1016/j.jaac.2012.02.018 · Cited by 333 · see citing works
“The meta-analysis was based on recommended guidelines.(27-29)”
Heterogeneity in Meta-Analyses of Genome-Wide Association Investigations
Ioannidis, J. P. A., Patsopoulos, N. A., & Εvangelou, Ε. (2007) · PLoS ONE · doi:10.1371/journal.pone.0000841 · Cited by 332 · see citing works
“Meta-analysis entails the combination of different studies or datasets on the same research question and meta-analytic methods have been used across many different scientific disciplines [1,2].”
BackgroundMethodInfluentialSelf-citation
- Authors
- Lau, J., Ioannidis, J. P. A., & Schmid, C. H.
- Affiliations
- Tufts University (US)
- Corresponding author
- Lau, Joseph
- Venue
- Annals of Internal Medicine
- Publisher
- American College of Physicians
- Published
- 1997-11-01
- Volume
- 127
- Issue
- 9
- Pages
- 820-826
- ISSN
- 0003-4819 (ISSN-L)
- 1539-3704
- OpenAlex
- W1982228885
- Cited by
- 2,517
- References
- 60
- Citations by year
- 2026: 40 · 2025: 48 · 2024: 67 · 2023: 45 · 2022: 96 · 2021: 104 · 2020: 112 · 2019: 131 · 2018: 126 · 2017: 165 · 2016: 161 · 2015: 202 · 2014: 186 · 2013: 181 · 2012: 134
- FWCI
- 36.48
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annals of Internal Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Agency for Healthcare Research and Quality (R01-HS07782, R01 HS08532)
- National Institute of Allergy and Infectious Diseases (T32AI07389, T32AI007389)
- Topics
- Social Sciences › Decision Sciences › Statistics, Probability and Uncertainty › Meta-analysis and systematic reviews
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Epidemiology
- Social Sciences › Sociology and Political Science › Delphi Technique in Research
- Keywords
- meta-analysis, systematic reviews, heterogeneity, fixed effects model, random effects models, meta-regression, sensitivity analysis, publication bias, study quality, diagnostic performance, observational studies
- MeSH terms
- Humans, Research Design, Statistics as Topic, Meta-Analysis as Topic, Bias, Randomized Controlled Trials as Topic
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