Pitfalls of and controversies in cluster randomization trials
Open accessAbstract
It is now well known that standard statistical procedures become invalidated when applied to cluster randomized trials in which the unit of inference is the individual. A resulting consequence is that researchers conducting such trials are faced with a multitude of design choices, including selection of the primary unit of inference, the degree to which clusters should be matched or stratified by prognostic factors at baseline, and decisions related to cluster subsampling. Moreover, application of ethical principles developed for individually randomized trials may also require modification. We discuss several topics related to these issues, with emphasis on the choices that must be made in the planning stages of a trial and on some potential pitfalls to be avoided.
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Cites
Applied Regression Analysis and Other Multivariable Methods
Walker, E., Kleinbaum, D. G., Kupper, L. L., & Muller, K. E. (1989) · Technometrics · doi:10.2307/1270375 · Cited by 8,538 · see citing works
Evaluating the public health impact of health promotion interventions: the RE-AIM framework.
Glasgow, R. E., Vogt, T. M., & Boles, S. M. (1999) · American Journal of Public Health · doi:10.2105/ajph.89.9.1322 · Cited by 7,217 · see citing works
Moher, D., Schulz, K. F., & Altman, D. G. (2001) · The Lancet · doi:10.1016/s0140-6736(00)04337-3 · Cited by 5,373 · see citing works
Moher, D., Schulz, K. F., & Altman, D. G. (2001) · BMC Medical Research Methodology · doi:10.1186/1471-2288-1-2 · Cited by 2,755 · see citing works
The strategy of preventive medicine
(1993) · Choice Reviews Online · doi:10.5860/choice.30-5633 · Cited by 1,878 · see citing works
Bringing context back into epidemiology: variables and fallacies in multilevel analysis
Diez-Roux, A. V. (1998) · American Journal of Public Health · doi:10.2105/ajph.88.2.216 · Cited by 1,317 · see citing works
Design and Analysis of Cluster Randomization Trials in Health Research
DONNER, A. P., & Klar, N. S. (2000) · Cited by 1,236 · see citing works
Self-citationWHO antenatal care randomised trial for the evaluation of a new model of routine antenatal care
Villar, J., Ba'aqeel, H., Piaggio, G., Lumbiganon, P., Belizán, J. M., Farnot, U., Al-Mazrou, Y., Carroli, G., Pinol, A., Donner, A., et al. (2001) · The Lancet · doi:10.1016/s0140-6736(00)04722-x · Cited by 627 · see citing works
Self-citationContamination in trials: is cluster randomisation the answer?
Torgerson, D. J. (2001) · BMJ · doi:10.1136/bmj.322.7282.355 · Cited by 508 · see citing works
Wr, L., Freedman, L., Green, S., Corle, D., Gail, M. H., Re, G., Hartwell, T., Km, C., Ockene, J., & Giffen, C. (1995) · American Journal of Public Health · doi:10.2105/ajph.85.2.183 · Cited by 452 · see citing works
Analysis of data from multiclinic trials
Fleiss, J. L. (1986) · Controlled Clinical Trials · doi:10.1016/0197-2456(86)90034-6 · Cited by 451 · see citing works
Vitamin A supplementation and child mortality. A meta-analysis
Fawzi, W. W. (1993) · JAMA · doi:10.1001/jama.269.7.898 · Cited by 396 · see citing works
Efficacy of vitamin A in reducing preschool child mortality in Nepal
West, K. P., Katz, J., LeClerq, S. C., Pradhan, E. K., Tielsch, J. M., Sommer, A. H., Pokhrel, R. P., Khatry, S. K., Shrestha, S. R., & Pandey, M. R. (1991) · The Lancet · doi:10.1016/0140-6736(91)90070-6 · Cited by 364 · see citing works
IMPLICATIONS OF THE RESULTS OF COMMUNITY INTERVENTION TRIALS
Sorensen, G., Emmons, K. M., Hunt, M. K., & Johnston, D. (1998) · Annual Review of Public Health · doi:10.1146/annurev.publhealth.19.1.379 · Cited by 314 · see citing works
Vitamin A Supplementation and Child Mortality
Fawzi, W. W. (1993) · JAMA · doi:10.1001/jama.1993.03500070078033 · Cited by 290 · see citing works
Randomized consent designs for clinical trials: An update
Zelen, M. (1990) · Statistics in Medicine · doi:10.1002/sim.4780090611 · Cited by 289 · see citing works
Ethical issues in the design and conduct of cluster randomised controlled trials
Edwards, S., Braunholtz, D., Lilford, R. J., & Stevens, A. J. (1999) · BMJ · doi:10.1136/bmj.318.7195.1407 · Cited by 253 · see citing works
ON DESIGN CONSIDERATIONS AND RANDOMIZATION-BASED INFERENCE FOR COMMUNITY INTERVENTION TRIALS
Gail, M. H., Mark, S. D., Carroll, R. J., Green, S. B., & Pee, D. (1996) · Statistics in Medicine · doi:10.1002/(sici)1097-0258(19960615)15:11 · Cited by 249 · see citing works
Cornfield, J. (1978) · American Journal of Epidemiology · doi:10.1093/oxfordjournals.aje.a112592 · Cited by 235 · see citing works
Statistical considerations in the design and analysis of community intervention trials
Donner, A., & Klar, N. (1996) · Journal of Clinical Epidemiology · doi:10.1016/0895-4356(95)00511-0 · Cited by 230 · see citing works
Self-citationStatistical methods for longitudinal and clustered designs with binary responses
Neuhaus, J. M. (1992) · Statistical Methods in Medical Research · doi:10.1177/096228029200100303 · Cited by 202 · see citing works
Koepsell, T. D., Wagner, E. H., Cheadle, A. D., Patrick, D. L., Martin, D. C., Diehr, P. H., Perrin, E. B., Kristal, A. R., Allan-Andrilla, C. H., & Dey, L. J. (1992) · Annual Review of Public Health · doi:10.1146/annurev.pu.13.050192.000335 · Cited by 193 · see citing works
Design and Interpretation of Vaccine Field Studies
Halloran, M. E., Longini, I. M., & Struchiner, C. J. (1999) · Epidemiologic Reviews · doi:10.1093/oxfordjournals.epirev.a017990 · Cited by 184 · see citing works
Designing and analysing case-control studies to exploit independence of genotype and exposure
Umbach, D. M., & Weinberg, C. R. (1997) · Statistics in Medicine · doi:10.1002/(sici)1097-0258(19970815)16:15 · Cited by 179 · see citing works
The Ethics of Biomedical Research: An International Perspective
Brody, B. A. (1998) · Cited by 174 · see citing works
Intraclass correlation coefficients for cluster randomized trials in primary care
Smeeth, L. L., & Ng, E. S.-W. (2002) · Controlled Clinical Trials · doi:10.1016/s0197-2456(02)00208-8 · Cited by 168 · see citing works
Design and analysis issues in cluster-randomized trials of interventions against infectious diseases
Hayes, R., Alexander, N. D. E., Bennett, S., & Cousens, S. N. (2000) · Statistical Methods in Medical Research · doi:10.1177/096228020000900203 · Cited by 160 · see citing works
Verstappen, W. H. J. M., van der Weijden, T., Sijbrandij, J., Smeele, I. J. M., Hermsen, J., Grimshaw, J., & Grol, R. P. T. M. (2003) · PubMed · doi:10.1001/jama.289.18.2407 · Cited by 160 · see citing works
DONNER, A. P., & Klar, N. S. (2000) · Statistical Methods in Medical Research · doi:10.1191/096228000669355658 · Cited by 149 · see citing works
Self-citationSelected Statistical Issues in Group Randomized Trials
Feng, Z., Diehr, P. H., Peterson, A. V., & McLerran, D. (2001) · Annual Review of Public Health · doi:10.1146/annurev.publhealth.22.1.167 · Cited by 144 · see citing works
Diehr, P. H., Martin, D. C., Koepsell, T. D., & Cheadle, A. D. (1995) · Statistics in Medicine · doi:10.1002/sim.4780141309 · Cited by 131 · see citing works
Clamp, M., & Kendrick, D. (1998) · BMJ · doi:10.1136/bmj.316.7144.1576 · Cited by 128 · see citing works
Cluster randomized trials in general (family) practice research
Campbell, M. J. (2000) · Statistical Methods in Medical Research · doi:10.1177/096228020000900202 · Cited by 113 · see citing works
The effect of matching on the power of randomized community intervention studies
Martin, D. C., Diehr, P. K., Perrin, E. B., & Koepsell, T. D. (1993) · Statistics in Medicine · doi:10.1002/sim.4780120315 · Cited by 106 · see citing works
Thompson, S. G., Pyke, S., & Hardy, R. (1997) · Statistics in Medicine · doi:10.1002/(sici)1097-0258(19970930)16:18 · Cited by 98 · see citing works
Ukoumunne, O. C. (2002) · Statistics in Medicine · doi:10.1002/sim.1330 · Cited by 96 · see citing works
Why does primary care need more implementation research?
Foy, R., Eccles, M., & Grimshaw, J. (2001) · Family Practice · doi:10.1093/fampra/18.4.353 · Cited by 96 · see citing works
Frangakis, C. (2002) · Biostatistics · doi:10.1093/biostatistics/3.2.147 · Cited by 94 · see citing works
Extending the CONSORT statement to cluster randomized trials: for discussion
Elbourne, D. R., & Campbell, M. (2001) · Statistics in Medicine · doi:10.1002/1097-0258(20010215)20:3 · Cited by 91 · see citing works
Donner, A. P., & Eliasziw, M. (1994) · Biometrics · doi:10.2307/2533400 · Cited by 66 · see citing works
Self-citationRay, W. A., Stein, C. M., Byrd, V. M., Shorr, R. I., Pichert, J. W., Gideon, P. S., Arnold, K., Brandt, K. D., Pincus, T., & Griffin, M. R. (2001) · Medical Care · doi:10.1097/00005650-200105000-00003 · Cited by 64 · see citing works
Lack of concealment may lead to selection bias in cluster randomized trials of palliative care
Jordhùy, M. S., Fayers, P. M., Ahlner‐Elmqvist, M., & Kaasa, S. (2002) · Palliative Medicine · doi:10.1191/0269216302pm523oa · Cited by 47 · see citing works
Farr, B. M., Hendley, J. O., Kaiser, D. L., & Gwaltney, J. M. (1988) · American Journal of Epidemiology · doi:10.1093/oxfordjournals.aje.a115059 · Cited by 39 · see citing works
Ethical Dilemmas in Health Promotion
Blaney, R., & Doxiadis, S. A. (1987) · Wiley eBooks · Cited by 28 · see citing works
Winkens, R. A. G., Knottnerus, J. A., Kester, A. D. M., Grol, R. P. T. M., & Pop, P. (1997) · Journal of Clinical Epidemiology · doi:10.1016/s0895-4356(96)00422-2 · Cited by 24 · see citing works
Sample size requirements for interval estimation of the intraclass kappa statistic
Allan, D. (1999) · Communications in Statistics - Simulation and Computation · doi:10.1080/03610919908813557 · Cited by 22 · see citing works
Cooperative Studies in Health Services Research in the Department of Veterans Affairs
Henderson, W. G., Demakis, J. G., Fihn, S. D., et al. (1998) · Controlled Clinical Trials · doi:10.1016/s0197-2456(97)00148-7 · Cited by 16 · see citing works
Selecting end point variables for a community intervention trial
Feldman, H. A. (1997) · Annals of Epidemiology · doi:10.1016/s1047-2797(97)80010-5 · Cited by 7 · see citing works
Estimating efficacy in clinical trials with clustered binary responses
Albert, J. M. (2002) · Statistics in Medicine · doi:10.1002/sim.1059 · Cited by 6 · see citing works
The ethics of ongoing randomization trials. Investigation among intimates.
Hi, G., & McGough, H. (1991) · PubMed · Cited by 6 · see citing works
Design and Analysis of Cluster Randomised Trials
Campbell, M. J., Elbourne, D. R., & DONNER, A. P. (2001) · Cited by 5 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 7
- [1]Cornfield J. Randomization by group: a formal analysis. Am J Epidemiol. 1978;108:100–102. [DOI] [PubMed] [Google Scholar]
- [7]Hutton JL. Are distinctive ethical principles required for cluster Randomized controlled trials? Stat Med. 2001;20:473–488. [DOI] [PubMed] [Google Scholar]
- [15]Feldman HA. Selecting endpoint variables for a community intervention trial. Ann Epidemiol. 1997;7(suppl):S78–S88. [Google Scholar]
- [23]Klar N, Donner A. The merits of matching in community intervention trials: a cautionary tale. Stat Med. 1997;16:1753–1764. [DOI] [PubMed] [Google Scholar]
- [26]Piantadosi S. Clinical Trials: A Methodologic Perspective. New York, NY: John Wiley & Sons Inc; 1997.
- [45]Murray DM. Design and Analysis of Group-Randomised Trials. New York, NY: Oxford University Press Inc; 1998.
- [48]Koepsell TD, Wagner EH, Cheadle AC, et al. Selected methodological issues in evaluating community-based health promotion programs. Annu Rev Public Health. 1992;13:13–57. [DOI] [PubMed] [Google Scholar]
Cited by
Sorted by citations
Des Jarlais, D. C., Lyles, C., Crepaz, N., & the TREND Group (2004) · American Journal of Public Health · doi:10.2105/ajph.94.3.361 · Cited by 2,817 · see citing works
Grant, A., Treweek, S., Dreischulte, T., Foy, R., & Guthrie, B. (2013) · Trials · doi:10.1186/1745-6215-14-15 · Cited by 541 · see citing works
Review of recent methodological developments in group-randomized trials: part 2—analysis
Turner, E. L., Prague, M., Gallis, J. A., Li, F., & Murray, D. M. (2017) · American Journal of Public Health · doi:10.2105/ajph.2017.303707 · Cited by 195 · see citing works
Ivers, N. M., Taljaard, M., Dixon, S., Bennett, C., McRae, A., Taleban, J., Skea, Z., Brehaut, J. C., Boruch, R. F., Eccles, M. P., et al. (2011) · BMJ · doi:10.1136/bmj.d5886 · Cited by 193 · see citing works
Self-citationAdaptive Designs for Randomized Trials in Public Health
Brown, C. H., Ten Have, T. R., Jo, B., Dagne, G., Wyman, P. A., Muthén, B., & Gibbons, R. D. (2009) · Annual Review of Public Health · doi:10.1146/annurev.publhealth.031308.100223 · Cited by 184 · see citing works
Li, P., & Redden, D. T. (2015) · BMC Medical Research Methodology · doi:10.1186/s12874-015-0026-x · Cited by 142 · see citing works
Using cluster bootstrapping to analyze nested data with a few clusters
Huang, F. L. (2018) · Educational and Psychological Measurement · doi:10.1177/0013164416678980 · Cited by 107 · see citing works
Sargeant, J. M., O’connor, A. M., Gardner, I. A., Dickson, J. S., Torrence, M. E., Dohoo, C. M. P. I. R., Lefebvre, S. L., Morley, P. S., Ramirez, A., & Snedeker, K. (2010) · Journal of Food Protection · doi:10.4315/0362-028x-73.3.579 · Cited by 97 · see citing works
Walwyn, R., & Roberts, C. (2010) · Statistical Methods in Medical Research · doi:10.1177/0962280209105017 · Cited by 93 · see citing works
Diaz-Ordaz, K., Froud, R., Sheehan, B., & Eldridge, S. (2013) · BMC Medical Research Methodology · doi:10.1186/1471-2288-13-127 · Cited by 47 · see citing works
Survey research methods in evaluation and case-control studies
Kalton, G., & Piesse, A. (2007) · Statistics in Medicine · doi:10.1002/sim.2796 · Cited by 27 · see citing works
Feedback on Oral Presentations During Pediatric Clerkships: A Randomized Controlled Trial
Sox, C. M., Dell, M., Phillipi, C. A., Cabral, H. J., Vargas, G., & Lewin, L. O. (2014) · Pediatrics · doi:10.1542/peds.2014-1209 · Cited by 19 · see citing works
Golzarri-Arroyo, L., Dickinson, S. L., Jamshidi-Naeini, Y., Zoh, R. S., Brown, A. W., Owora, A. H., Li, P., Oakes, J. M., & Allison, D. B. (2022) · Computer Methods and Programs in Biomedicine · doi:10.1016/j.cmpb.2022.106654 · Cited by 9 · see citing works
Tekwe, C. D., & Allison, D. B. (2020) · Annals of Behavioral Medicine · doi:10.1093/abm/kaz065 · Cited by 3 · see citing works
- Authors
- Donner, A., & Klar, N.
- Affiliations
- Western University (CA)
- ORCID
- Klar, Neil
- Venue
- American Journal of Public Health
- Publisher
- American Public Health Association
- Published
- 2004-03
- Volume
- 94
- Issue
- 3
- Pages
- 416-422
- ISSN
- 0090-0036 (ISSN-L)
- 1541-0048
- PMC
- PMC1448267
- OpenAlex
- W2097334037
- Cited by
- 442
- References
- 51
- Citations by year
- 2026: 10 · 2025: 28 · 2024: 16 · 2023: 19 · 2022: 21 · 2021: 30 · 2020: 15 · 2019: 39 · 2018: 22 · 2017: 20 · 2016: 27 · 2015: 20 · 2014: 18 · 2013: 23 · 2012: 23
- FWCI
- 11.14
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Public Health (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Physical Sciences › Mathematics › Statistics and Probability › Advanced Causal Inference Techniques
- Social Sciences › Decision Sciences › Statistics, Probability and Uncertainty › Meta-analysis and systematic reviews
- Keywords
- cluster matching, prognostic factors, trial design, ethical principles, statistical validity
- MeSH terms
- Humans, Informed Consent, Models, Statistical, Epidemiologic Research Design, Public Health Practice, Bias, Cluster Analysis, Randomized Controlled Trials as Topic, Sample Size
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