0
October 23, 1996, Vol 276, No. 16 >
ARTICLE | October 23, 1996

Large Trials vs Meta-analysis of Smaller Trials: Title and subTitle BreakHow Do Their Results Compare? FREE

Joseph C. Cappelleri, PhD, MPH; John P. A. loannidis, MD; Christopher H. Schmid, PhD; Sarah D. de Ferranti, MD, MPH; Michael Aubert; Thomas C. Chalmers, MD; Joseph Lau, MD
[+] Author Affiliations

†Deceased.

Reprints: Joseph Lau, MD, New England Medical Center, PO Box 63, 750 Washington St, Boston, MA 02111.


JAMA. 1996;276(16):1332-1338. doi:10.1001/jama.1996.03540160054033
Text Size: A A A
Published online
Article
References

Objective.  —To evaluate the results of large clinical trials vs the pooled results of smaller trials.

Data Identification.  —Mata-analyses with at least 1 "large" study were identified from the Cochrane Pregnancy and Childbirth Database and from MEDLINE (1966-1995).

Study Selection.  —We used a sample size approach to select 79 meta-analyses with at least 1 large study of 1000 or more patients. We used a statistical power approach to select 61 meta-analyses with at least 1 large study based on statistical power considerations.

Data Extraction.  —The outcome of interest for each meta-analysis was the primary one stated in the original publication or, when not clearly specified, was decided on clinically.

Data Synthesis.  —By random effects calculations, we found agreement between large and smaller trials in 90% of the meta-analyses selected by the sample size approach and in 82% of the meta-analyses selected by the statistical power approach. Twice as many disagreements appeared when the variability among large studies and among smaller studies was not considered (ie, fixed effects calculations). Of the 15 disagreements between results of large and smaller trials using the random effects model, plausible explanations were identified in 10 meta-analyses: 5 with differences in the control rate of events between large and smaller trials, 4 with specific protocol or study differences, and 1 with potential publication bias. Two other disagreements were not clinically important, and tentative reasons could be identified for 2 of the remaining 3 disagreements.

Conclusion.  —Results of smaller studies are usually compatible with the results of large studies, but discrepancies do occur even when the diversity among both large studies and smaller studies is considered. Clinically important differences without a potential explanation are extremely uncommon. Future research should further examine sources of heterogeneity between the results of large and smaller trials.

REFERENCES

1 +
Lau J, Antman EM, Jimenez-Silva J, Kupelnick B, Mosteller F, Chalmers TC.  Cumulative metaanalysis of therapeutic trials for myocardial infarction . N Engl J Med . 1992;;327:248-254.
2 +
Lau J, Chalmers TC.  Should intravenous magnesium be given to patients with acute myocardial infarction? Clin Res . 1994;;42:290A.
3 +
Borzak S, Ridker PM.  Discordance between metaanalyses and large-scale randomized, control trials . Ann Intern Med . 1995;;123:873-877.
4 +
Domanski MJ, Friedman LM.  Relative role of metaanalysis and randomized controlled trials in the assessment of medical therapies . Am J Cardiol . 1994;;74:395-396.
5 +
Woods KL.  Mega-trials and management of acute myocardial infarction . Lancet . 1995;;346:611-614.
6 +
Yusuf S, Flather M.  Magnesium in acute myocardial infarction . BMJ . 1995;;310:751-752.
7 +
Egger M, Davey Smith G.  Misleading meta-analysis . BMJ . 1995;;310:752-754.
8 +
Morris JL, Cowan Campbell J.  Nitrates in myocardial infarction: a current perspective . Can J Cardiol . 1995;;11:5B-10B.
9 +
Chalmers TC, Levin H, Sacks HS, Reitman D, Berrier J, Nagalingam R.  Meta-analysis of clinical trials as a scientific discipline, I: control of bias and comparison with large co-operative trials . Stat Med . 1987;;6:315-325.
10 +
Villar J, Carroli G, Belizan JM.  Predictive ability of meta-analyses of randomised controlled trials . Lancet . 1995;;345:772-776.
11 +
Flournoy N, Olkin I.  Do small trials square with large ones? Lancet . 1995;;345:741-742.
12 +
Lumley T, Keech A.  Meta-meta-analysis with confidence . Lancet . 1995;;346:576-577.
13 +
Gonser M, Vetter K, Noack F.  Meta-analyses of interventional trials done in populations with different risks . Lancet . 1995;;345:1304-1305.
14 +
Enkin MW, Keirse MJNC, Renfrew MJ, Neilson JP, eds. Pregnancy and Childbirth Module: Cochrane Database of Systematic Reviews (Cochrane Updates on Disk) . Oxford, England: Update Software; 1994;. Disk issue 1.
15 +
Johnson EG, Tukey JW,  Graphical exploratory analysis of variance illustrated on a splitting of the Johnson and Tsao data . In: Mallows CL, ed. Design, Data, and Analysis: By Some Friends of Cuthbert Daniel . New York, NY: John Wiley & Sons; 1987;: 171-244.
16 +
Dean AG, Dean JA, Burton AH, Dicker RC. Epi Info, Version 5: A Word Processing, Database, and Statistics Program for Epidemiology on Microcomputers. Atlanta, Ga: Centers for Disease Control; 1990.
17 +
Rothman KJ. Modern Epidemiology . Boston, Mass: Little Brown & Co; 1986;:177-236.
18 +
Ioannidis JPA, Cappelleri JC, Lau J, et al.  Early or deferred zidovudine therapy in HIV-infected patients without an AIDS-defining illness: a metaanalysis . Ann Intern Med . 1995;;122:856-866.
19 +
Schmid CH, McIntosh M, Cappelleri JC, Lau J, Chalmers TC.  Measuring the impact of the control rate in meta-analysis of clinical trials . Control Clin Trials . 1995;;16:66S.
20 +
Antman EM.  Randomized trials of magnesium in acute myocardial infarction: big numbers do not tell the whole story . Am J Cardiol . 1995;;75:391-393.
21 +
Thompson SG.  Controversies in meta-analysis: the case of the trials of serum cholesterol reduction . Stat Methods Med Res . 1993;;2:173-192.
22 +
Smith GD, Song F, Sheldon RA.  Cholesterol lowering and mortality: the importance of considering initial level of risk . BMJ . 1993;;306:1367-1373.
23 +
Boissel JP, Collet JP, Lievre M, Girard P.  An effect model for the assessment of drug benefit: example of antiarrhythmic drugs in postmyocardial infarction patients . J Cardiovasc Pharmacol . 1993;;22:356-363.
24 +
Abramson JH. Making Sense of Data: A Selfinstruction Manual on the Interpretation of Epidemiologic Data . 2nd ed. New York, NY: Oxford University Press; 1994;:319-389.
25 +
Rotwell M.  Can overall results of clinical trials be applied to all patients? Lancet . 1995;;345:1616-1619.
26 +
Dempster AP, Laird NM, Rubin DB.  Maximum likelihood from incomplete data via the EM algorithm . J R Stat Soc . 1977;;38:1-22.
27 +
McIntosh M.  The population risk as an explanatory variable in research synthesis of clinical trials . Stat Med . 1996;;15:1713-1728.
28 +
Cox DR, Snell EJ. Analysis of Binary Data . 2nd ed. New York, NY: Chapman & Hall; 1989;:19-20.
29 +
Begg CB, Mazumdar M.  Operating characteristics of a rank correlation test for publication bias . Biometrics . 1994;;50:1088-1101.
30 +
Lau J. Meta-Analyst . Version 0.988. Boston, Mass: New England Medical Center; 1995;.
31 +
MathSoft, Inc. Mathcad Plus 6.0 . Cambridge, Mass: MathSoft Inc; 1995;.
32 +
Statistical Sciences Inc. S- PLUS User's Manual. Version 3.2. Seattle, Wash: StatSci, MathSoft Inc; 1993.
33 +
SAS Institute Inc. The SAS System for Windows. Version 6.10. Cary, NC: SAS Institute Inc; 1994.
34 +
Halliday HL.  Overview of clinical trials comparing natural and synthetic surfactants . Biol Neonate . 1995;:67( (suppl 1) ):32-47.
35 +
ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group.  ISIS-4: a randomized factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58050 patients in suspected acute myocardial infarction . Lancet . 1995;;345:669-685.
36 +
Jovell AJ, Lau J, Berkey C, Kupelnick B, Chalmers TC.  Early angiography and angioplasty following thrombolytic therapy of acute myocardial infarction: metaanalyses of the randomized control trials . Online J Curr Clin Trials [serial online]. (June 5) , 1993;; doc 67.
37 +
Basinki A, Naylor CD.  Aspirin and fibrinolysis in acute myocardial infarction: meta-analytic evidence for synergy . J Clin Epidemiol . 1991;;44:1085-1096.
38 +
Naylor CD, Jaglal SB.  Impact of intravenous thrombolysis on short-term coronary revascularization rates: a meta-analysis . JAMA . 1990;;264:697-702.
39 +
Antiplatelet Trialists' Collaboration.  Collaborative overview of randomised trials of antiplatelet therapy, I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients . BMJ . 1994;;308:81-106.
40 +
Barnett HJM, Eliasziw M, Meldrum HE.  Drugs and surgery in the prevention of ischemic stroke . N Engl J Med . 1995;;332:238-248.
41 +
Pocock SJ, Henderson RA, Rickards AF, et al.  Meta-analysis of randomised trials comparing coronary angioplasty with bypass surgery . Lancet . 1995;;346:1184-1189.
42 +
Cappelleri JC, Lau J, Kupelnick B, Chalmers TC.  Efficacy and safety of different aspirin dosages on vascular diseases: a meta-regression analysis . Online J Curr Clin Trials [serial online]. (March 14) , 1995;; doc 174.
43 +
Early Breast Cancer Trialists' Collaborative Group.  Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomised trials involving 31000 recurrences and 24 000 deaths among 75000 women . Lancet . 1992;;339:1-15, 71-85.
44 +
Early Breast Cancer Trialists' Collaborative Group.  Effects of radiotherapy and surgery in early breast cancer: an overview of the randomized trials . N Engl J Med . 1995;;333:1444-1455.
45 +
Leizorovicz A, Haugh MC, Chapuis FR, Samama MM, Boissel JP.  Low molecular weight heparin in prevention of perioperative thrombosis . BMJ . 1992;;305:913-920.
46 +
Antiplatelet Trialists' Collaboration.  Collaborative overview of randomised trials of antiplatelet therapy, III: reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients . BMJ . 1994;;308:235-246.
47 +
Antiplatelet Trialists' Collaboration.  Collaborative overview of randomised trials of antiplatelet therapy, II: maintenance of vascular graft or arterial patency by antiplatelet therapy . BMJ . 1994;;308:159-168.
48 +
Insua JT, Sacks HS, Lau TS, et al.  Drug treatment of hypertension in the elderly: a meta-analysis . Ann Intern Med . 1994;;121:355-362.
49 +
Collins R, Peto R, MacMahon S, et al.  Blood pressure, stroke and coronary heart disease, II: short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context . Lancet . 1990;;335:827-838.
50 +
Garg R, Yusuf S, for the Collaborative Group on ACE Inhibitor Trials.  Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure . JAMA . 1995;;273:1450-1456.
51 +
Nony P, Boissel JP, Lievre M, et al.  Evaluation of the effect of phosphodiesterase inhibitors on mortality in chronic heart failure patients: a meta-analysis . Eur J Clin Pharmacol . 1994;;46:191-196.
52 +
Glasziou PP, Mackerras DEM.  Vitamin A supplementation in infectious diseases: a meta-analysis . BMJ . 1993;;306:366-370.
53 +
Berkey CS, Hoaglin DC, Mosteller F, Colditz GA.  A random-effects regression model for metaanalysis . Stat Med . 1995;;14:395-411.
54 +
Fiore MC, Smith SS, Jorenby DE, Baker TB.  The effectiveness of the nicotine patch for smoking cessation: a meta-analysis . JAMA . 1994;;271:1940-1947.
55 +
Belizan JM, Villar J, Gonzalez L, Campodonico L, Bergel E.  Calcium supplementation to prevent hypertensive disorders of pregnancy . N Engl J Med . 1991;;325:1399-1405.
56 +
Khan KS, Daya S, Jadad AR.  The importance of quality of primary studies in producing unbiased systematic reviews . Arch Intern Med . 1996;;156:661-666.
57 +
Sinclair JC, Bracken MB.  Clinically useful measures of effect in binary analyses of randomized trials . J Clin Epidemiol . 1994;;47:881-889.
58 +
Hedges LV.  Fixed effects models . In: Cooper H, Hedges LV, eds. The Handbook of Research Synthesis . New York, NY: Russell Sage Foundation; 1994;:285-299.
59 +
Raudenbush SW.  Random effects models . In: Cooper H, Hedges LV, eds. The Handbook of Research Synthesis . New York, NY: Russell Sage Foundation; 1994;:301-321.
60 +
Peto R, Collins R, Gray R.  Large-scale randomized evidence: large, simple trials and overviews of trials . In: Warren KS, Mosteller F, eds. Doing More Good Than Harm: The Evaluation of Health Care Interventions . New York, NY: New York Academy of Sciences; 1993;:314-340.
61 +
Sackett DL, Cook DJ.  Can we learn anything from small trials?  In: Warren KS, Mosteller F, eds. Doing More Good Than Harm: The Evaluation of Health Care Interventions . New York, NY: New York Academy of Sciences; 1993;:25-31.
62 +
Yusuf S, Collins R, Peto R.  Why do we need some large, simple randomized trials? Stat Med . 1984;;3: 409-420.

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Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature

Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

1 +
Lau J, Antman EM, Jimenez-Silva J, Kupelnick B, Mosteller F, Chalmers TC.  Cumulative metaanalysis of therapeutic trials for myocardial infarction . N Engl J Med . 1992;;327:248-254.
2 +
Lau J, Chalmers TC.  Should intravenous magnesium be given to patients with acute myocardial infarction? Clin Res . 1994;;42:290A.
3 +
Borzak S, Ridker PM.  Discordance between metaanalyses and large-scale randomized, control trials . Ann Intern Med . 1995;;123:873-877.
4 +
Domanski MJ, Friedman LM.  Relative role of metaanalysis and randomized controlled trials in the assessment of medical therapies . Am J Cardiol . 1994;;74:395-396.
5 +
Woods KL.  Mega-trials and management of acute myocardial infarction . Lancet . 1995;;346:611-614.
6 +
Yusuf S, Flather M.  Magnesium in acute myocardial infarction . BMJ . 1995;;310:751-752.
7 +
Egger M, Davey Smith G.  Misleading meta-analysis . BMJ . 1995;;310:752-754.
8 +
Morris JL, Cowan Campbell J.  Nitrates in myocardial infarction: a current perspective . Can J Cardiol . 1995;;11:5B-10B.
9 +
Chalmers TC, Levin H, Sacks HS, Reitman D, Berrier J, Nagalingam R.  Meta-analysis of clinical trials as a scientific discipline, I: control of bias and comparison with large co-operative trials . Stat Med . 1987;;6:315-325.
10 +
Villar J, Carroli G, Belizan JM.  Predictive ability of meta-analyses of randomised controlled trials . Lancet . 1995;;345:772-776.
11 +
Flournoy N, Olkin I.  Do small trials square with large ones? Lancet . 1995;;345:741-742.
12 +
Lumley T, Keech A.  Meta-meta-analysis with confidence . Lancet . 1995;;346:576-577.
13 +
Gonser M, Vetter K, Noack F.  Meta-analyses of interventional trials done in populations with different risks . Lancet . 1995;;345:1304-1305.
14 +
Enkin MW, Keirse MJNC, Renfrew MJ, Neilson JP, eds. Pregnancy and Childbirth Module: Cochrane Database of Systematic Reviews (Cochrane Updates on Disk) . Oxford, England: Update Software; 1994;. Disk issue 1.
15 +
Johnson EG, Tukey JW,  Graphical exploratory analysis of variance illustrated on a splitting of the Johnson and Tsao data . In: Mallows CL, ed. Design, Data, and Analysis: By Some Friends of Cuthbert Daniel . New York, NY: John Wiley & Sons; 1987;: 171-244.
16 +
Dean AG, Dean JA, Burton AH, Dicker RC. Epi Info, Version 5: A Word Processing, Database, and Statistics Program for Epidemiology on Microcomputers. Atlanta, Ga: Centers for Disease Control; 1990.
17 +
Rothman KJ. Modern Epidemiology . Boston, Mass: Little Brown & Co; 1986;:177-236.
18 +
Ioannidis JPA, Cappelleri JC, Lau J, et al.  Early or deferred zidovudine therapy in HIV-infected patients without an AIDS-defining illness: a metaanalysis . Ann Intern Med . 1995;;122:856-866.
19 +
Schmid CH, McIntosh M, Cappelleri JC, Lau J, Chalmers TC.  Measuring the impact of the control rate in meta-analysis of clinical trials . Control Clin Trials . 1995;;16:66S.
20 +
Antman EM.  Randomized trials of magnesium in acute myocardial infarction: big numbers do not tell the whole story . Am J Cardiol . 1995;;75:391-393.
21 +
Thompson SG.  Controversies in meta-analysis: the case of the trials of serum cholesterol reduction . Stat Methods Med Res . 1993;;2:173-192.
22 +
Smith GD, Song F, Sheldon RA.  Cholesterol lowering and mortality: the importance of considering initial level of risk . BMJ . 1993;;306:1367-1373.
23 +
Boissel JP, Collet JP, Lievre M, Girard P.  An effect model for the assessment of drug benefit: example of antiarrhythmic drugs in postmyocardial infarction patients . J Cardiovasc Pharmacol . 1993;;22:356-363.
24 +
Abramson JH. Making Sense of Data: A Selfinstruction Manual on the Interpretation of Epidemiologic Data . 2nd ed. New York, NY: Oxford University Press; 1994;:319-389.
25 +
Rotwell M.  Can overall results of clinical trials be applied to all patients? Lancet . 1995;;345:1616-1619.
26 +
Dempster AP, Laird NM, Rubin DB.  Maximum likelihood from incomplete data via the EM algorithm . J R Stat Soc . 1977;;38:1-22.
27 +
McIntosh M.  The population risk as an explanatory variable in research synthesis of clinical trials . Stat Med . 1996;;15:1713-1728.
28 +
Cox DR, Snell EJ. Analysis of Binary Data . 2nd ed. New York, NY: Chapman & Hall; 1989;:19-20.
29 +
Begg CB, Mazumdar M.  Operating characteristics of a rank correlation test for publication bias . Biometrics . 1994;;50:1088-1101.
30 +
Lau J. Meta-Analyst . Version 0.988. Boston, Mass: New England Medical Center; 1995;.
31 +
MathSoft, Inc. Mathcad Plus 6.0 . Cambridge, Mass: MathSoft Inc; 1995;.
32 +
Statistical Sciences Inc. S- PLUS User's Manual. Version 3.2. Seattle, Wash: StatSci, MathSoft Inc; 1993.
33 +
SAS Institute Inc. The SAS System for Windows. Version 6.10. Cary, NC: SAS Institute Inc; 1994.
34 +
Halliday HL.  Overview of clinical trials comparing natural and synthetic surfactants . Biol Neonate . 1995;:67( (suppl 1) ):32-47.
35 +
ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group.  ISIS-4: a randomized factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58050 patients in suspected acute myocardial infarction . Lancet . 1995;;345:669-685.
36 +
Jovell AJ, Lau J, Berkey C, Kupelnick B, Chalmers TC.  Early angiography and angioplasty following thrombolytic therapy of acute myocardial infarction: metaanalyses of the randomized control trials . Online J Curr Clin Trials [serial online]. (June 5) , 1993;; doc 67.
37 +
Basinki A, Naylor CD.  Aspirin and fibrinolysis in acute myocardial infarction: meta-analytic evidence for synergy . J Clin Epidemiol . 1991;;44:1085-1096.
38 +
Naylor CD, Jaglal SB.  Impact of intravenous thrombolysis on short-term coronary revascularization rates: a meta-analysis . JAMA . 1990;;264:697-702.
39 +
Antiplatelet Trialists' Collaboration.  Collaborative overview of randomised trials of antiplatelet therapy, I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients . BMJ . 1994;;308:81-106.
40 +
Barnett HJM, Eliasziw M, Meldrum HE.  Drugs and surgery in the prevention of ischemic stroke . N Engl J Med . 1995;;332:238-248.
41 +
Pocock SJ, Henderson RA, Rickards AF, et al.  Meta-analysis of randomised trials comparing coronary angioplasty with bypass surgery . Lancet . 1995;;346:1184-1189.
42 +
Cappelleri JC, Lau J, Kupelnick B, Chalmers TC.  Efficacy and safety of different aspirin dosages on vascular diseases: a meta-regression analysis . Online J Curr Clin Trials [serial online]. (March 14) , 1995;; doc 174.
43 +
Early Breast Cancer Trialists' Collaborative Group.  Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomised trials involving 31000 recurrences and 24 000 deaths among 75000 women . Lancet . 1992;;339:1-15, 71-85.
44 +
Early Breast Cancer Trialists' Collaborative Group.  Effects of radiotherapy and surgery in early breast cancer: an overview of the randomized trials . N Engl J Med . 1995;;333:1444-1455.
45 +
Leizorovicz A, Haugh MC, Chapuis FR, Samama MM, Boissel JP.  Low molecular weight heparin in prevention of perioperative thrombosis . BMJ . 1992;;305:913-920.
46 +
Antiplatelet Trialists' Collaboration.  Collaborative overview of randomised trials of antiplatelet therapy, III: reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients . BMJ . 1994;;308:235-246.
47 +
Antiplatelet Trialists' Collaboration.  Collaborative overview of randomised trials of antiplatelet therapy, II: maintenance of vascular graft or arterial patency by antiplatelet therapy . BMJ . 1994;;308:159-168.
48 +
Insua JT, Sacks HS, Lau TS, et al.  Drug treatment of hypertension in the elderly: a meta-analysis . Ann Intern Med . 1994;;121:355-362.
49 +
Collins R, Peto R, MacMahon S, et al.  Blood pressure, stroke and coronary heart disease, II: short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context . Lancet . 1990;;335:827-838.
50 +
Garg R, Yusuf S, for the Collaborative Group on ACE Inhibitor Trials.  Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure . JAMA . 1995;;273:1450-1456.
51 +
Nony P, Boissel JP, Lievre M, et al.  Evaluation of the effect of phosphodiesterase inhibitors on mortality in chronic heart failure patients: a meta-analysis . Eur J Clin Pharmacol . 1994;;46:191-196.
52 +
Glasziou PP, Mackerras DEM.  Vitamin A supplementation in infectious diseases: a meta-analysis . BMJ . 1993;;306:366-370.
53 +
Berkey CS, Hoaglin DC, Mosteller F, Colditz GA.  A random-effects regression model for metaanalysis . Stat Med . 1995;;14:395-411.
54 +
Fiore MC, Smith SS, Jorenby DE, Baker TB.  The effectiveness of the nicotine patch for smoking cessation: a meta-analysis . JAMA . 1994;;271:1940-1947.
55 +
Belizan JM, Villar J, Gonzalez L, Campodonico L, Bergel E.  Calcium supplementation to prevent hypertensive disorders of pregnancy . N Engl J Med . 1991;;325:1399-1405.
56 +
Khan KS, Daya S, Jadad AR.  The importance of quality of primary studies in producing unbiased systematic reviews . Arch Intern Med . 1996;;156:661-666.
57 +
Sinclair JC, Bracken MB.  Clinically useful measures of effect in binary analyses of randomized trials . J Clin Epidemiol . 1994;;47:881-889.
58 +
Hedges LV.  Fixed effects models . In: Cooper H, Hedges LV, eds. The Handbook of Research Synthesis . New York, NY: Russell Sage Foundation; 1994;:285-299.
59 +
Raudenbush SW.  Random effects models . In: Cooper H, Hedges LV, eds. The Handbook of Research Synthesis . New York, NY: Russell Sage Foundation; 1994;:301-321.
60 +
Peto R, Collins R, Gray R.  Large-scale randomized evidence: large, simple trials and overviews of trials . In: Warren KS, Mosteller F, eds. Doing More Good Than Harm: The Evaluation of Health Care Interventions . New York, NY: New York Academy of Sciences; 1993;:314-340.
61 +
Sackett DL, Cook DJ.  Can we learn anything from small trials?  In: Warren KS, Mosteller F, eds. Doing More Good Than Harm: The Evaluation of Health Care Interventions . New York, NY: New York Academy of Sciences; 1993;:25-31.
62 +
Yusuf S, Collins R, Peto R.  Why do we need some large, simple randomized trials? Stat Med . 1984;;3: 409-420.

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