CoChat
Sign Up
Cited by 257Meta-analysis and systematic reviewsStatistical Methods in Clinical TrialsPharmaceutical industry and healthcare

Empirical Evaluation of Very Large Treatment Effects of Medical Interventions

Pereira, Tiago V., Horwitz, Ralph I., Ioannidis, John P. A.·2012·JAMA
DOI 10.1001/jama.2012.13444
Open this paper in CoChat — free account

Abstract

CONTEXT: Most medical interventions have modest effects, but occasionally some clinical trials may find very large effects for benefits or harms. OBJECTIVE: To evaluate the frequency and features of very large effects in medicine. DATA SOURCES: Cochrane Database of Systematic Reviews (CDSR, 2010, issue 7). STUDY SELECTION: We separated all binary-outcome CDSR forest plots with comparisons of interventions according to whether the first published trial, a subsequent trial (not the first), or no trial had a nominally statistically significant (P < .05) very large effect (odds ratio [OR], ≥5). We also sampled randomly 250 topics from each group for further in-depth evaluation. DATA EXTRACTION: We assessed the types of treatments and outcomes in trials with very large effects, examined how often large-effect trials were followed up by other trials on the same topic, and how these effects compared against the effects of the respective meta-analyses. RESULTS: Among 85,002 forest plots (from 3082 reviews), 8239 (9.7%) had a significant very large effect in the first published trial, 5158 (6.1%) only after the first published trial, and 71,605 (84.2%) had no trials with significant very large effects. Nominally significant very large effects typically appeared in small trials with median number of events: 18 in first trials and 15 in subsequent trials. Topics with very large effects were less likely than other topics to address mortality (3.6% in first trials, 3.2% in subsequent trials, and 11.6% in no trials with significant very large effects) and were more likely to address laboratory-defined efficacy (10% in first trials,10.8% in subsequent, and 3.2% in no trials with significant very large effects). First trials with very large effects were as likely as trials with no very large effects to have subsequent published trials. Ninety percent and 98% of the very large effects observed in first and subsequently published trials, respectively, became smaller in meta-analyses that included other trials; the median odds ratio decreased from 11.88 to 4.20 for first trials, and from 10.02 to 2.60 for subsequent trials. For 46 of the 500 selected topics (9.2%; first and subsequent trials) with a very large-effect trial, the meta-analysis maintained very large effects with P < .001 when additional trials were included, but none pertained to mortality-related outcomes. Across the whole CDSR, there was only 1 intervention with large beneficial effects on mortality, P < .001, and no major concerns about the quality of the evidence (for a trial on extracorporeal oxygenation for severe respiratory failure in newborns). CONCLUSIONS: Most large treatment effects emerge from small studies, and when additional trials are performed, the effect sizes become typically much smaller. Well-validated large effects are uncommon and pertain to nonfatal outcomes.

Integrity signals

Registry

Crossref · 10.1001/jama.2012.13444

Cites

37 of 37 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

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?

Cites

3 retracted

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Pereira, T. V., Horwitz, R. I., & Ioannidis, J. P. A.
Affiliations
Hospital Alemão Oswaldo Cruz (BR)
Corresponding author
Ioannidis, John P. A.
ORCID
Venue
JAMA
Publisher
American Medical Association (AMA)
Published
2012-10-24
Volume
308
Issue
16
Pages
1676
ISSN
  • 0002-9955 (ISSN-L)
  • 0098-7484
DOI
10.1001/jama.2012.13444
OpenAlex
W2065177605
Cited by
257
References
37
Citations by year
2026: 11 · 2025: 24 · 2024: 15 · 2023: 15 · 2022: 10 · 2021: 22 · 2020: 12 · 2019: 14 · 2018: 12 · 2017: 27 · 2016: 17 · 2015: 31 · 2014: 24 · 2013: 21 · 2012: 2
FWCI
28.38
Type
journal article
Language
en
Open access
closed
Locations
  • JAMA (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
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmaceutical industry and healthcare
Keywords
odds ratio, meta-analysis heterogeneity, publication bias, forest plots, mortality, treatment effect heterogeneity, medical interventions, harms of interventions, evidence-based policy, evidence-based care
MeSH terms
Data Interpretation, Statistical, Meta-Analysis as Topic, Odds Ratio, Randomized Controlled Trials as Topic, Treatment Outcome, Sample Size, Empirical Research

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