The DOI matches its Crossref record; 72 of the 72 references it cites were found in a registry or an index.
Single-Center Trials Show Larger Treatment Effects Than Multicenter Trials: Evidence From a Meta-epidemiologic Study
Abstract
BACKGROUND: A recent study suggested that results of single-center trials are frequently contradicted when similar trials are performed in multicenter settings. PURPOSE: To perform a meta-epidemiologic study to evaluate whether estimates of treatment effect differ between single-center and multicenter randomized, controlled trials (RCTs). DATA SOURCES: MEDLINE was searched via PubMed for meta-analyses of RCTs with binary outcomes that were published between August 2008 and January 2009 and in the first 6 months of 2010 in the 10 leading journals of each medical specialty. One issue of the Cochrane Database of Systematic Reviews was also searched. STUDY SELECTION: All individual RCTs included in the meta-analyses were selected. DATA EXTRACTION: Data were extracted and their quality was assessed by use of the risk of bias tool of the Cochrane Collaboration. DATA SYNTHESIS: The primary outcome was the ratio of odds ratios (ROR), used to quantify the difference in estimated intervention effect between single-center and multicenter RCTs. An ROR less than 1 would indicate larger estimates of the intervention effect in single-center trials. Sensitivity analyses were performed with adjustment for sample size, risk of bias within RCTs, and variance of the log odds ratio to take publication bias into account. Forty-eight meta-analyses were selected, including 421 RCTs (223 were single-center and 198 were multicenter). Single-center RCTs showed a larger intervention effect than did multicenter RCTs (combined ROR, 0.73 [95% CI, 0.64 to 0.83]), with low heterogeneity across individual meta-analyses (I(2) = 12.0%; P = 0.24). Adjustment for sample size yielded consistent results (ROR, 0.85 [CI, 0.74 to 0.97]), as did adjustment for risk of bias within RCTs, such as allocation concealment (ROR, 0.76 [CI, 0.67 to 0.86]), and variance of log odds ratio (ROR, 0.83 [CI, 0.72 to 0.96]). LIMITATION: Despite sensitivity analyses, meta-confounding cannot be fully excluded. CONCLUSION: Single-center RCTs showed larger treatment effects than did multicenter RCTs, a finding that was consistent in all sensitivity analyses. These results suggest that this item should be considered when the results of RCTs and meta-analyses are interpreted. PRIMARY FUNDING SOURCE: Academic grant Recherche sur la Recherche from the Délégation Interrégionale à la Recherche Clinique (DIRC), Ile de France, Assistance Publique-Hôpitaux de Paris (APHP).
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Although most included studies were conducted at a single center, which may result in a more significant treatment effect and risk of bias 28 , we identified many cross-country collaborations.”
From Global mapping of randomized controlled trials in dentistry (2024) · cites this paper as [28]
Citations
Cites
Schulz (1995) · doi:10.1001/jama.1995.03520290060030 · Cited by 5,634
Moher, D., Pham, B., Jones, A., Cook, D. J., Jadad, A. R., Moher, M., Tugwell, P., & Klassen, T. P. (1998) · The Lancet · doi:10.1016/s0140-6736(98)01085-x · Cited by 3,560
Assessing the quality of controlled clinical trials
Jüni, P., Altman, D. G., & Egger, M. (2001) · BMJ · doi:10.1136/bmj.323.7303.42 · Cited by 3,309 · cited 1×
“The amount of the difference was substantial, with a relative increase of 27% in the intervention effect estimate for single-center RCTs as compared with multicenter RCTs; this result is similar to the bias induced by unclear or inadequate allocation concealment (10).”
ResultWood, L., Egger, M., Gluud, L. L., Schulz, K. F., Jüni, P., Altman, D. G., Gluud, C., Martin, R. M., Wood, A. J. G., & Sterne, J. A. C. (2008) · BMJ · doi:10.1136/bmj.39465.451748.ad · Cited by 2,538
Publication and related bias in meta-analysis
Sterne, J. A. C., Gavaghan, D., & Egger, M. (2000) · Journal of Clinical Epidemiology · doi:10.1016/s0895-4356(00)00242-0 · Cited by 2,282
What to add to nothing? Use and avoidance of continuity corrections in meta‐analysis of sparse data
J. Sweeting, M., J. Sutton, A., & C. Lambert, P. (2004) · Statistics in Medicine · doi:10.1002/sim.1761 · Cited by 1,734
Publication bias: evidence of delayed publication in a cohort study of clinical research projects
Stern, J. M., & Simes, R. J. (1997) · BMJ · doi:10.1136/bmj.315.7109.640 · Cited by 818
BAUJAT, B., Mahé, C., Pignon, J., & Hill, C. (2002) · Statistics in Medicine · doi:10.1002/sim.1221 · Cited by 798
Bias in clinical intervention research.
Gluud, L. L. (2006) · American Journal of Epidemiology · doi:10.1093/aje/kwj069 · Cited by 636
Chan, A.-W., & Altman, D. G. (2005) · BMJ · doi:10.1136/bmj.38356.424606.8f · Cited by 613
Singh, S. (2008) · JAMA · doi:10.1001/jama.300.12.1439 · Cited by 493
Impact of allocation concealment on conclusions drawn from meta-analyses of randomized trials
Pildal, J., Hrobjartsson, A., Jorgensen, K., Hilden, J., Altman, D., & Gotzsche, P. (2007) · International Journal of Epidemiology · doi:10.1093/ije/dym087 · Cited by 472
Preventing the Onset of Depressive Disorders: A Meta-Analytic Review of Psychological Interventions
Cuijpers, P., van Straten, A., Smit, F., Mihalopoulos, C., & Beekman, A. (2008) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2008.07091422 · Cited by 456 · cited 3×
“…et al, 2010 (43) Subtotal (I2 = 3.3%; Phet = 0.42; τ2 = 0.005) Nonpharmacologic interventions Bechtold et al, 2008 (44) Cennamo et al, 2010 (45) Cuijpers et al, 2008 (46) De Luca et al, 2008 (47) El-Toukhy et al, 2008 (48) Fairchild et al, 2008 (49) Jones et al, 2008 (50) Karthikesalingam et…”
BackgroundInfluentialStem cell treatment for acute myocardial infarction
Fisher, S. A., Zhang, H., Doree, C. J., Mathur, A., & Martin‐Rendon, E. (2015) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd006536.pub4 · Cited by 445
Publication Bias: The Problem That Won't Go Away
DICKERSIN, K., & MIN, Y. (1993) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1993.tb26343.x · Cited by 427
Prevention of Atrial Fibrillation by Renin-Angiotensin System Inhibition
Schneider, M. P., Hua, T. A., Böhm, M., Wachtell, K., Kjeldsen, S. E., & Schmieder, R. E. (2010) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2010.01.043 · Cited by 417
Laine, L., & McQuaid, K. R. (2008) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2008.08.016 · Cited by 388
Sterne, J. A. C., Jüni, P., Schulz, K. F., Altman, D. G., Bartlett, C., & Egger, M. (2002) · Statistics in Medicine · doi:10.1002/sim.1184 · Cited by 382
Moreno, S. G., Sutton, A. J., Ades, A., Stanley, T. D., Abrams, K. R., Peters, J. L., & Cooper, N. J. (2009) · BMC Medical Research Methodology · doi:10.1186/1471-2288-9-2 · Cited by 373
Why we should be wary of single-center trials
Bellomo, R., Warrillow, S. J., & Reade, M. C. (2009) · Critical Care Medicine · doi:10.1097/ccm.0b013e3181bc7bd5 · Cited by 367
Toward Understanding Tight Glycemic Control in the ICU
Marik, P. E., & Preiser, J.-C. (2010) · Chest · doi:10.1378/chest.09-1737 · Cited by 365
Inhaled Corticosteroids in Patients With Stable Chronic Obstructive Pulmonary Disease
Drummond, M., Dasenbrook, E. C., Pitz, M. W., Murphy, D. J., & Fan, E. (2008) · JAMA · doi:10.1001/jama.2008.717 · Cited by 362
Horvath, K., Koch, K., Jeitler, K., Matyas, E., Bender, R., Bastian, H., Lange, S., & Siebenhofer, A. (2010) · BMJ · doi:10.1136/bmj.c1395 · Cited by 359
Perioperative β blockers in patients having non-cardiac surgery: a meta-analysis
Bangalore, S., Wetterslev, J., Pranesh, S., Sawhney, S., Gluud, C. N., & Messerli, F. H. (2008) · The Lancet · doi:10.1016/s0140-6736(08)61560-3 · Cited by 355
Mupirocin ointment for preventing Staphylococcus aureus infections in nasal carriers
van Rijen, M., Bonten, M. J. M., Wenzel, R. P., & Kluytmans, J. A. J. W. (2008) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd006216.pub2 · Cited by 286
Association of Journal Quality Indicators With Methodological Quality of Clinical Research Articles
Lee, K. P. (2002) · JAMA · doi:10.1001/jama.287.21.2805 · Cited by 284
Tan, J. A., & Ho, K. M. (2010) · Intensive Care Medicine · doi:10.1007/s00134-010-1877-6 · Cited by 282
Palliative thoracic radiotherapy for lung cancer: a systematic review.
Fairchild, A., Harris, K., Barnes, E., Wong, R., Lutz, S., Bezjak, A., Cheung, P., & Chow, E. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2007.15.3312 · Cited by 266
Novara, G., Antonio Galfano, A., Secco, S., D’Elia, C., Cavalleri, S., Ficarra, V., & Artibani, W. (2008) · European Urology · doi:10.1016/j.eururo.2008.06.080 · Cited by 266
Luca, G. D., Dudek, D., Sardella, G., Marino, P. N., Chevalier, B., & Zijlstra, F. (2008) · European Heart Journal · doi:10.1093/eurheartj/ehn389 · Cited by 259
Meta-analysis: Noninvasive Ventilation in Acute Cardiogenic Pulmonary Edema
Weng, C., Zhao, Y.-T., Liu, Q.-H., Fu, C.-J., Sun, F., Ma, Y.-L., Chen, Y.-W., & He, Q.-Y. (2010) · Annals of Internal Medicine · doi:10.7326/0003-4819-152-9-201005040-00009 · Cited by 258
Nuesch, E., Trelle, S., Reichenbach, S., Rutjes, A. W. S., Burgi, E., Scherer, M., Altman, D. G., & Juni, P. (2009) · BMJ · doi:10.1136/bmj.b3244 · Cited by 248 · cited 1×
“Risk of bias Sequence generation High 5 (2) 0 (0) Low 75 (34) 90 (45) Unclear 143 (64) 108 (55) Allocation concealment High 8 (4) 1 (1) Low 32 (14) 68 (34) Unclear 183 (82) 129 (65) Blinding High 72 (32) 41 (21) Low 151 (68) 157 (79) Unclear 0 (0) 0 (0) Incomplete outcome data High 16 (7) 48 (24) Low 68 (31) 55 (28) U…”
Sud, S., Sud, M. K., Friedrich, J. O., Meade, M., Ferguson, N. D., Wunsch, H., & Adhikari, N. K. J. (2010) · BMJ · doi:10.1136/bmj.c2327 · Cited by 245
Vitamin D treatment for the prevention of falls in older adults: systematic review and meta-analysis
Kalyani, R. R., Stein, B., Valiyil, R., Manno, R., Maynard, J. W., & Crews, D. C. (2010) · Journal of the American Geriatrics Society · doi:10.1111/j.1532-5415.2010.02949.x · Cited by 241
Craen, K. V., Braes, T., Wellens, N. I. H., Denhaerynck, K., Flamaing, J., Moons, P., Boonen, S., Gosset, C., Pétermans, J., & Milisen, K. (2009) · Journal of the American Geriatrics Society · doi:10.1111/j.1532-5415.2009.02621.x · Cited by 236
Investigating patient exclusion bias in meta-analysis
Tierney, J. F. (2004) · International Journal of Epidemiology · doi:10.1093/ije/dyh300 · Cited by 221
Schömig, A., Mehilli, J., de Waha, A., Seyfarth, M., Pache, J., & Kastrati, A. (2008) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2008.05.051 · Cited by 211
Cennamo, V., Fuccio, L., Zagari, R., et al. (2010) · Endoscopy · doi:10.1055/s-0029-1243992 · Cited by 209
Siempos, I. I., Ntaidou, T. K., & Falagas, M. E. (2010) · Critical Care Medicine · doi:10.1097/ccm.0b013e3181c8fe4b · Cited by 204
Jones, A. E., Brown, M. D., Trzeciak, S., Shapiro, N. I., Garrett, J. S., Heffner, A. C., & Kline, J. A. (2008) · Critical Care Medicine · doi:10.1097/ccm.0b013e318186f839 · Cited by 197
Surgery for primary supratentorial intracerebral haemorrhage
Prasad, K., Mendelow, A. D., & GREGSON, B. A. (2008) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd000200.pub2 · Cited by 187
Ziakas, P. D., Pavlou, M., & Voulgarelis, M. (2010) · Obstetrics & Gynecology · doi:10.1097/aog.0b013e3181deba40 · Cited by 185
Karthikesalingam, A., Markar, S. R., Holt, P. J. E., & Praseedom, R. K. (2010) · Journal of British Surgery · doi:10.1002/bjs.6902 · Cited by 173
Lin, P., Chang, C., Hsu, P., Tseng, P.-L., & Huang, Y. (2010) · Critical Care Medicine · doi:10.1097/ccm.0b013e3181d69ccf · Cited by 173
Mollon, B., da Silva, V., Busse, J. W., Einhorn, T. A., & Bhandari, M. (2008) · Journal of Bone and Joint Surgery · doi:10.2106/jbjs.h.00111 · Cited by 163
Meier, P., Knapp, G., Tamhane, U. U., Chaturvedi, S., & Gurm, H. S. (2010) · BMJ · doi:10.1136/bmj.c467 · Cited by 158
Efficacy of Intra-Arterial Fibrinolysis for Acute Ischemic Stroke
Lee, M., Hong, K., & Saver, J. L. (2010) · Stroke · doi:10.1161/strokeaha.109.574335 · Cited by 157
Boutron, I. (2003) · JAMA · doi:10.1001/jama.290.8.1062 · Cited by 155
Self-citationEfficacy of Homocysteine-Lowering Therapy With Folic Acid in Stroke Prevention
Lee, M., Hong, K., Chang, S., & Saver, J. L. (2010) · Stroke · doi:10.1161/strokeaha.109.573410 · Cited by 154
Cooper, N. A. M., Khan, K. S., & Clark, T. J. (2010) · BMJ · doi:10.1136/bmj.c1130 · Cited by 154
Desmopressin Reduces Transfusion Needs after Surgery
Crescenzi, G., Landoni, G., Biondi‐Zoccai, G., Pappalardo, F., Nuzzi, M., Bignami, E. G., Fochi, O., Maj, G., Calabró, M. G., Ranucci, M., et al. (2008) · Anesthesiology · doi:10.1097/aln.0b013e31818db18b · Cited by 146
An Assessment of Publication Bias Using a Sample of Published Clinical Trials
Berlin, J. A., Begg, C. B., & Louis, T. A. (1989) · Journal of the American Statistical Association · doi:10.1080/01621459.1989.10478782 · Cited by 134
Randomized clinical trials in Hepatology: Predictors of quality
Gluud, L. L., Nikolova, D., & Gluud, C. N. (1999) · Hepatology · doi:10.1002/hep.510300510 · Cited by 115
Falagas, M. E., Giannopoulou, K., Vardakas, K. Z., Dimοpoulos, G., & Karageorgopoulos, D. E. (2008) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(08)70202-0 · Cited by 114
Blümle, A., Huwiler, K., & Witschi, M. (2008) · Swiss Medical Weekly · doi:10.4414/smw.2008.12027 · Cited by 114
A systematic review and meta‐analysis of acupuncture in in vitro fertilisation
El‐Toukhy, T., Sunkara, S. K., Khairy, M., Dyer, R., Khalaf, Y., & Coomarasamy, A. (2008) · BJOG An International Journal of Obstetrics & Gynaecology · doi:10.1111/j.1471-0528.2008.01838.x · Cited by 112
Feller, M., Huwiler, K., Schoepfer, A. M., Shang, A., Furrer, H., & Egger, M. (2010) · Clinical Infectious Diseases · doi:10.1086/649923 · Cited by 105
Riddle, M. S., Arnold, S., & Tribble, D. R. (2008) · Clinical Infectious Diseases · doi:10.1086/591703 · Cited by 100
Kasapis, C., Henke, P. K., Chetcuti, S. J., Koenig, G. C., Rectenwald, J. E., Krishnamurthy, V. N., Grossman, P. M., & Gurm, H. S. (2008) · European Heart Journal · doi:10.1093/eurheartj/ehn514 · Cited by 99
Fernández-Guisasola, J., Gómez-Arnau, J. I., Cabrera, Y., & del Valle, S. G. (2010) · Anaesthesia · doi:10.1111/j.1365-2044.2010.06249.x · Cited by 97
Wang, C. (2010) · Archives of Internal Medicine · doi:10.1001/archinternmed.2010.100 · Cited by 96
Lourenço, T., Pickard, R., Vale, L. D., et al. (2008) · BMJ · doi:10.1136/bmj.a1662 · Cited by 88
Fan, T., Wang, G., Mao, B., et al. (2008) · BMJ · doi:10.1136/bmj.a1841 · Cited by 87
Bechtold, M. L., Matteson, M., Choudhary, A., et al. (2008) · The American Journal of Gastroenterology · doi:10.1111/j.1572-0241.2008.02108.x · Cited by 80
Tsoi, D. T.-Y., Porwal, M., & Webster, A. C. (2010) · The British Journal of Psychiatry · doi:10.1192/bjp.bp.109.066019 · Cited by 77
Kuriya, B., Arkema, E. V., Bykerk, V. P., et al. (2010) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2009.118307 · Cited by 70
Meta-analysis of N-Acetylcysteine to Prevent Acute Renal Failure After Major Surgery
Ho, K. M., & Morgan, D. J. R. (2008) · American Journal of Kidney Diseases · doi:10.1053/j.ajkd.2008.05.019 · Cited by 63
Friedman, B. W., Kapoor, A., Friedman, M. S., et al. (2008) · Annals of Emergency Medicine · doi:10.1016/j.annemergmed.2008.05.036 · Cited by 49
Piscione, F., Piccolo, R., Cassese, S., Galasso, G., D’Andrea, C., Rosa, R. D., & Chiariello, M. (2010) · Heart · doi:10.1136/hrt.2009.183277 · Cited by 46
The quality of reporting of randomized controlled trials in solid organ transplantation
Pengel, L. H. M., Barcena, L., & Morris, P. J. (2008) · Transplant International · doi:10.1111/j.1432-2277.2008.00789.x · Cited by 33
Biau, D. J., Halm, J. A., Ahmadieh, H., et al. (2008) · Annals of Surgery · doi:10.1097/sla.0b013e31816ffa99 · Cited by 28
Brandler, E. S., Paladino, L., & Sinert, R. H. (2010) · Academic Emergency Medicine · doi:10.1111/j.1553-2712.2009.00625.x · Cited by 27
Research works printed but not linked: 4
- van Rijen M, 2008, Cochrane Database Syst Rev, CD006216
- Martin-Rendon E, 2008, Cochrane Database Syst Rev, CD006536
- Prasad K, 2008, Cochrane Database Syst Rev, CD000200
- von Elm E, 2008, Swiss Med Wkly, 138, 197
Cited by
Sorted by citations
Shamseer, L., Moher, D., Clarke, M., Ghersi, D., Liberati, A., Petticrew, M., Shekelle, P., Stewart, L. A., & the PRISMA-P Group (2015) · BMJ · doi:10.1136/bmj.g7647 · Cited by 13,120
Savović, J., Jones, H. E., Altman, D. G., Harris, R. J., Jüni, P., Pildal, J., Als-Nielsen, B., Balk, E. M., Gluud, C., Gluud, L. L., et al. (2012) · Annals of Internal Medicine · doi:10.7326/0003-4819-157-6-201209180-00537 · Cited by 1,049
Messier, S. P., Mihalko, S. L., Legault, C., Miller, G. D., Nicklas, B. J., DeVita, P., Beavers, D. P., Hunter, D. J., Lyles, M. F., Eckstein, F., et al. (2013) · JAMA · doi:10.1001/jama.2013.277669 · Cited by 873
Influence of trial sample size on treatment effect estimates: meta-epidemiological study
Dechartres, A., Trinquart, L., Boutron, I., & Ravaud, P. (2013) · BMJ · doi:10.1136/bmj.f2304 · Cited by 544
Self-citationPrevalence of anxiety in Parkinson's disease: A systematic review and meta‐analysis
Broen, M. P. G., Narayen, N. E., Kuijf, M. L., Dissanayaka, N. N. W., & Leentjens, A. F. G. (2016) · Movement Disorders · doi:10.1002/mds.26643 · Cited by 457
Metadata
- Authors
- Dechartres, A., Boutron, I., Trinquart, L., Charles, P., & Ravaud, P.
- Affiliations
- From U738 INSERM; Assistance Publique Hôpitaux de Paris (APHP), Hôpital Hôtel-Dieu; Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine; and French Cochrane Centre, Paris, France, and Hôpital Foch, Suresnes, France.
- Inserm (FR)
- Venue
- Annals of Internal Medicine
- Publisher
- American College of Physicians
- Published
- 2011-07-05
- Volume
- 155
- Issue
- 1
- Pages
- 39-51
- ISSN
- 0003-4819 (ISSN-L)
- 1539-3704
- OpenAlex
- W2072619571
- Cited by
- 307
- References
- 72
- Citations by year
- 2026: 14 · 2025: 16 · 2024: 22 · 2023: 19 · 2022: 37 · 2021: 27 · 2020: 14 · 2019: 16 · 2018: 13 · 2017: 22 · 2016: 24 · 2015: 19 · 2014: 23 · 2013: 20 · 2012: 19
- FWCI
- 21.79
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annals of Internal Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Social Sciences › Decision Sciences › Statistics, Probability and Uncertainty › Meta-analysis and systematic reviews
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Health Sciences › Nursing › Issues, ethics and legal aspects › Pharmaceutical industry and healthcare
- Keywords
- single-center trials, treatment effect estimates, meta-epidemiology, publication bias, allocation concealment, risk of bias, binary outcomes, sample size adjustment
- MeSH terms
- Humans, Sensitivity and Specificity, Meta-Analysis as Topic, Multicenter Studies as Topic, Epidemiologic Research Design, Bias, Odds Ratio, Randomized Controlled Trials as Topic, Treatment Outcome, Sample Size
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review