Power failure: why small sample size undermines the reliability of neuroscience (original) (raw)
Ioannidis, J. P. Why most published research findings are false. PLoS Med.2, e124 (2005). This study demonstrates that many (and possibly most) of the conclusions drawn from biomedical research are probably false. The reasons for this include using flexible study designs and flexible statistical analyses and running small studies with low statistical power. ArticlePubMedPubMed Central Google Scholar
Fanelli, D. Negative results are disappearing from most disciplines and countries. Scientometrics90, 891–904 (2012). Article Google Scholar
Greenwald, A. G. Consequences of prejudice against the null hypothesis. Psychol. Bull.82, 1–20 (1975). Article Google Scholar
Nosek, B. A., Spies, J. R. & Motyl, M. Scientific utopia: II. Restructuring incentives and practices to promote truth over publishability. Perspect. Psychol. Sci.7, 615–631 (2012). ArticlePubMed Google Scholar
Simmons, J. P., Nelson, L. D. & Simonsohn, U. False-positive psychology: undisclosed flexibility in data collection and analysis allows presenting anything as significant. Psychol. Sci.22, 1359–1366 (2011). This article empirically illustrates that flexible study designs and data analysis dramatically increase the possibility of obtaining a nominally significant result. However, conclusions drawn from these results are almost certainly false. ArticlePubMed Google Scholar
Begley, C. G. & Ellis, L. M. Drug development: raise standards for preclinical cancer research. Nature483, 531–533 (2012). ArticleCASPubMed Google Scholar
Prinz, F., Schlange, T. & Asadullah, K. Believe it or not: how much can we rely on published data on potential drug targets? Nature Rev. Drug Discov.10, 712 (2011). ArticleCAS Google Scholar
Munafo, M. R., Stothart, G. & Flint, J. Bias in genetic association studies and impact factor. Mol. Psychiatry14, 119–120 (2009). ArticleCASPubMed Google Scholar
Ioannidis, J. P. A., Tarone, R. & McLaughlin, J. K. The false-positive to false-negative ratio in epidemiologic studies. Epidemiology22, 450–456 (2011). ArticlePubMed Google Scholar
Ioannidis, J. P. A. Why most discovered true associations are inflated. Epidemiology19, 640–648 (2008). ArticlePubMed Google Scholar
Tversky, A. & Kahneman, D. Belief in the law of small numbers. Psychol. Bull.75, 105–110 (1971). Article Google Scholar
Masicampo, E. J. & Lalande, D. R. A peculiar prevalence of p values just below .05. Q. J. Exp. Psychol.65, 2271–2279 (2012). ArticleCAS Google Scholar
Carp, J. The secret lives of experiments: methods reporting in the fMRI literature. Neuroimage63, 289–300 (2012). This article reviews methods reporting and methodological choices across 241 recent fMRI studies and shows that there were nearly as many unique analytical pipelines as there were studies. In addition, many studies were underpowered to detect plausible effects. ArticlePubMed Google Scholar
Dwan, K. et al. Systematic review of the empirical evidence of study publication bias and outcome reporting bias. PLoS ONE3, e3081 (2008). ArticleCASPubMedPubMed Central Google Scholar
Sterne, J. A. et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ343, d4002 (2011). ArticlePubMed Google Scholar
Joy-Gaba, J. A. & Nosek, B. A. The surprisingly limited malleability of implicit racial evaluations. Soc. Psychol.41, 137–146 (2010). Article Google Scholar
Schmidt, K. & Nosek, B. A. Implicit (and explicit) racial attitudes barely changed during Barack Obama's presidential campaign and early presidency. J. Exp. Soc. Psychol.46, 308–314 (2010). Article Google Scholar
Evangelou, E., Siontis, K. C., Pfeiffer, T. & Ioannidis, J. P. Perceived information gain from randomized trials correlates with publication in high-impact factor journals. J. Clin. Epidemiol.65, 1274–1281 (2012). ArticlePubMed Google Scholar
Pereira, T. V. & Ioannidis, J. P. Statistically significant meta-analyses of clinical trials have modest credibility and inflated effects. J. Clin. Epidemiol.64, 1060–1069 (2011). ArticlePubMed Google Scholar
Faul, F., Erdfelder, E., Lang, A. G. & Buchner, A. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav. Res. Methods39, 175–191 (2007). ArticlePubMed Google Scholar
Babbage, D. R. et al. Meta-analysis of facial affect recognition difficulties after traumatic brain injury. Neuropsychology25, 277–285 (2011). ArticlePubMed Google Scholar
Bai, H. Meta-analysis of 5, 10-methylenetetrahydrofolate reductase gene poymorphism as a risk factor for ischemic cerebrovascular disease in a Chinese Han population. Neural Regen. Res.6, 277–285 (2011). Google Scholar
Bjorkhem-Bergman, L., Asplund, A. B. & Lindh, J. D. Metformin for weight reduction in non-diabetic patients on antipsychotic drugs: a systematic review and meta-analysis. J. Psychopharmacol.25, 299–305 (2011). ArticlePubMed Google Scholar
Bucossi, S. et al. Copper in Alzheimer's disease: a meta-analysis of serum, plasma, and cerebrospinal fluid studies. J. Alzheimers Dis.24, 175–185 (2011). ArticleCASPubMed Google Scholar
Chamberlain, S. R. et al. Translational approaches to frontostriatal dysfunction in attention-deficit/hyperactivity disorder using a computerized neuropsychological battery. Biol. Psychiatry69, 1192–1203 (2011). ArticlePubMed Google Scholar
Chang, W. P., Arfken, C. L., Sangal, M. P. & Boutros, N. N. Probing the relative contribution of the first and second responses to sensory gating indices: a meta-analysis. Psychophysiology48, 980–992 (2011). ArticlePubMed Google Scholar
Chang, X. L. et al. Functional parkin promoter polymorphism in Parkinson's disease: new data and meta-analysis. J. Neurol. Sci.302, 68–71 (2011). ArticleCASPubMed Google Scholar
Chen, C. et al. Allergy and risk of glioma: a meta-analysis. Eur. J. Neurol.18, 387–395 (2011). ArticleCASPubMed Google Scholar
Chung, A. K. & Chua, S. E. Effects on prolongation of Bazett's corrected QT interval of seven second-generation antipsychotics in the treatment of schizophrenia: a meta-analysis. J. Psychopharmacol.25, 646–666 (2011). ArticlePubMed Google Scholar
Domellof, E., Johansson, A. M. & Ronnqvist, L. Handedness in preterm born children: a systematic review and a meta-analysis. Neuropsychologia49, 2299–2310 (2011). ArticlePubMed Google Scholar
Etminan, N., Vergouwen, M. D., Ilodigwe, D. & Macdonald, R. L. Effect of pharmaceutical treatment on vasospasm, delayed cerebral ischemia, and clinical outcome in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. J. Cereb. Blood Flow Metab.31, 1443–1451 (2011). ArticleCASPubMedPubMed Central Google Scholar
Feng, X. L. et al. Association of FK506 binding protein 5 (FKBP5) gene rs4713916 polymorphism with mood disorders: a meta-analysis. Acta Neuropsychiatr.23, 12–19 (2011). ArticlePubMed Google Scholar
Green, M. J., Matheson, S. L., Shepherd, A., Weickert, C. S. & Carr, V. J. Brain-derived neurotrophic factor levels in schizophrenia: a systematic review with meta-analysis. Mol. Psychiatry16, 960–972 (2011). ArticleCASPubMed Google Scholar
Han, X. M., Wang, C. H., Sima, X. & Liu, S. Y. Interleukin-6–74G/C polymorphism and the risk of Alzheimer's disease in Caucasians: a meta-analysis. Neurosci. Lett.504, 4–8 (2011). ArticleCASPubMed Google Scholar
Hannestad, J., DellaGioia, N. & Bloch, M. The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: a meta-analysis. Neuropsychopharmacology36, 2452–2459 (2011). ArticleCASPubMedPubMed Central Google Scholar
Hua, Y., Zhao, H., Kong, Y. & Ye, M. Association between the MTHFR gene and Alzheimer's disease: a meta-analysis. Int. J. Neurosci.121, 462–471 (2011). ArticleCASPubMed Google Scholar
Lindson, N. & Aveyard, P. An updated meta-analysis of nicotine preloading for smoking cessation: investigating mediators of the effect. Psychopharmacology214, 579–592 (2011). ArticleCASPubMed Google Scholar
Liu, H. et al. Association of 5-HTT gene polymorphisms with migraine: a systematic review and meta-analysis. J. Neurol. Sci.305, 57–66 (2011). ArticleCASPubMed Google Scholar
Liu, J. et al. PITX3 gene polymorphism is associated with Parkinson's disease in Chinese population. Brain Res.1392, 116–120 (2011). ArticleCASPubMed Google Scholar
Maneeton, N., Maneeton, B., Srisurapanont, M. & Martin, S. D. Bupropion for adults with attention-deficit hyperactivity disorder: meta-analysis of randomized, placebo-controlled trials. Psychiatry Clin. Neurosci.65, 611–617 (2011). ArticlePubMed Google Scholar
Ohi, K. et al. The SIGMAR1 gene is associated with a risk of schizophrenia and activation of the prefrontal cortex. Prog. Neuropsychopharmacol. Biol. Psychiatry35, 1309–1315 (2011). ArticleCASPubMed Google Scholar
Olabi, B. et al. Are there progressive brain changes in schizophrenia? A meta-analysis of structural magnetic resonance imaging studies. Biol. Psychiatry70, 88–96 (2011). ArticlePubMed Google Scholar
Oldershaw, A. et al. The socio-emotional processing stream in Anorexia Nervosa. Neurosci. Biobehav. Rev.35, 970–988 (2011). ArticleCASPubMed Google Scholar
Oliver, B. J., Kohli, E. & Kasper, L. H. Interferon therapy in relapsing-remitting multiple sclerosis: a systematic review and meta-analysis of the comparative trials. J. Neurol. Sci.302, 96–105 (2011). ArticleCASPubMed Google Scholar
Peerbooms, O. L. et al. Meta-analysis of MTHFR gene variants in schizophrenia, bipolar disorder and unipolar depressive disorder: evidence for a common genetic vulnerability? Brain Behav. Immun.25, 1530–1543 (2011). ArticleCASPubMed Google Scholar
Pizzagalli, D. A. Frontocingulate dysfunction in depression: toward biomarkers of treatment response. Neuropsychopharmacology36, 183–206 (2011). ArticlePubMed Google Scholar
Rist, P. M., Diener, H. C., Kurth, T. & Schurks, M. Migraine, migraine aura, and cervical artery dissection: a systematic review and meta-analysis. Cephalalgia31, 886–896 (2011). ArticlePubMedPubMed Central Google Scholar
Sexton, C. E., Kalu, U. G., Filippini, N., Mackay, C. E. & Ebmeier, K. P. A meta-analysis of diffusion tensor imaging in mild cognitive impairment and Alzheimer's disease. Neurobiol. Aging32, 2322.e5–2322.e18 (2011). Article Google Scholar
Shum, D., Levin, H. & Chan, R. C. Prospective memory in patients with closed head injury: a review. Neuropsychologia49, 2156–2165 (2011). ArticlePubMed Google Scholar
Sim, H. et al. Acupuncture for carpal tunnel syndrome: a systematic review of randomized controlled trials. J. Pain12, 307–314 (2011). ArticlePubMed Google Scholar
Sun, Q. L. et al. Correlation of E-selectin gene polymorphisms with risk of ischemic stroke A meta-analysis. Neural Regen. Res.6, 1731–1735 (2011). CAS Google Scholar
Tian, Y., Kang, L. G., Wang, H. Y. & Liu, Z. Y. Meta-analysis of transcranial magnetic stimulation to treat post-stroke dysfunction. Neural Regen. Res.6, 1736–1741 (2011). Google Scholar
Trzesniak, C. et al. Adhesio interthalamica alterations in schizophrenia spectrum disorders: a systematic review and meta-analysis. Prog. Neuropsychopharmacol. Biol. Psychiatry35, 877–886 (2011). ArticlePubMed Google Scholar
Veehof, M. M., Oskam, M. J., Schreurs, K. M. & Bohlmeijer, E. T. Acceptance-based interventions for the treatment of chronic pain: a systematic review and meta-analysis. Pain152, 533–542 (2011). ArticlePubMed Google Scholar
Vergouwen, M. D., Etminan, N., Ilodigwe, D. & Macdonald, R. L. Lower incidence of cerebral infarction correlates with improved functional outcome after aneurysmal subarachnoid hemorrhage. J. Cereb. Blood Flow Metab.31, 1545–1553 (2011). ArticlePubMedPubMed Central Google Scholar
Vieta, E. et al. Effectiveness of psychotropic medications in the maintenance phase of bipolar disorder: a meta-analysis of randomized controlled trials. Int. J. Neuropsychopharmacol.14, 1029–1049 (2011). ArticleCASPubMed Google Scholar
Wisdom, N. M., Callahan, J. L. & Hawkins, K. A. The effects of apolipoprotein E on non-impaired cognitive functioning: a meta-analysis. Neurobiol. Aging32, 63–74 (2011). ArticleCASPubMed Google Scholar
Witteman, J., van Ijzendoorn, M. H., van de Velde, D., van Heuven, V. J. & Schiller, N. O. The nature of hemispheric specialization for linguistic and emotional prosodic perception: a meta-analysis of the lesion literature. Neuropsychologia49, 3722–3738 (2011). ArticlePubMed Google Scholar
Woon, F. & Hedges, D. W. Gender does not moderate hippocampal volume deficits in adults with posttraumatic stress disorder: a meta-analysis. Hippocampus21, 243–252 (2011). ArticlePubMed Google Scholar
Xuan, C. et al. No association between APOE ε 4 allele and multiple sclerosis susceptibility: a meta-analysis from 5472 cases and 4727 controls. J. Neurol. Sci.308, 110–116 (2011). ArticleCASPubMed Google Scholar
Yang, W. M., Kong, F. Y., Liu, M. & Hao, Z. L. Systematic review of risk factors for progressive ischemic stroke. Neural Regen. Res.6, 346–352 (2011). Google Scholar
Yang, Z., Li, W. J., Huang, T., Chen, J. M. & Zhang, X. Meta-analysis of Ginkgo biloba extract for the treatment of Alzheimer's disease. Neural Regen. Res.6, 1125–1129 (2011). CAS Google Scholar
Yuan, H. et al. Meta-analysis of tau genetic polymorphism and sporadic progressive supranuclear palsy susceptibility. Neural Regen. Res.6, 353–359 (2011). Google Scholar
Zafar, S. N., Iqbal, A., Farez, M. F., Kamatkar, S. & de Moya, M. A. Intensive insulin therapy in brain injury: a meta-analysis. J. Neurotrauma28, 1307–1317 (2011). ArticlePubMed Google Scholar
Zhang, Y. G. et al. The −1082G/A polymorphism in IL-10 gene is associated with risk of Alzheimer's disease: a meta-analysis. J. Neurol. Sci.303, 133–138 (2011). ArticleCASPubMed Google Scholar
Zhu, Y., He, Z. Y. & Liu, H. N. Meta-analysis of the relationship between homocysteine, vitamin B(12), folate, and multiple sclerosis. J. Clin. Neurosci.18, 933–938 (2011). ArticleCASPubMed Google Scholar
Ioannidis, J. P. & Trikalinos, T. A. An exploratory test for an excess of significant findings. Clin. Trials4, 245–253 (2007). This study describes a test that evaluates whether there is an excess of significant findings in the published literature. The number of expected studies with statistically significant results is estimated and compared against the number of observed significant studies. ArticlePubMed Google Scholar
Ioannidis, J. P. Excess significance bias in the literature on brain volume abnormalities. Arch. Gen. Psychiatry68, 773–780 (2011). ArticlePubMed Google Scholar
Pfeiffer, T., Bertram, L. & Ioannidis, J. P. Quantifying selective reporting and the Proteus phenomenon for multiple datasets with similar bias. PLoS ONE6, e18362 (2011). ArticleCASPubMedPubMed Central Google Scholar
Tsilidis, K. K., Papatheodorou, S. I., Evangelou, E. & Ioannidis, J. P. Evaluation of excess statistical significance in meta-analyses of 98 biomarker associations with cancer risk. J. Natl Cancer Inst.104, 1867–1878 (2012). ArticleCASPubMed Google Scholar
Ioannidis, J. Clarifications on the application and interpretation of the test for excess significance and its extensions. J. Math. Psychol. (in the press).
David, S. P. et al. Potential reporting bias in small fMRI studies of the brain. PLoS Biol. (in the press).
Sena, E. S., van der Worp, H. B., Bath, P. M., Howells, D. W. & Macleod, M. R. Publication bias in reports of animal stroke studies leads to major overstatement of efficacy. PLoS Biol.8, e1000344 (2010). ArticleCASPubMedPubMed Central Google Scholar
Ioannidis, J. P. Extrapolating from animals to humans. Sci. Transl. Med.4, 151ps15 (2012). ArticlePubMed Google Scholar
Jonasson, Z. Meta-analysis of sex differences in rodent models of learning and memory: a review of behavioral and biological data. Neurosci. Biobehav. Rev.28, 811–825 (2005). ArticlePubMed Google Scholar
Macleod, M. R. et al. Evidence for the efficacy of NXY-059 in experimental focal cerebral ischaemia is confounded by study quality. Stroke39, 2824–2829 (2008). ArticlePubMed Google Scholar
Sena, E., van der Worp, H. B., Howells, D. & Macleod, M. How can we improve the pre-clinical development of drugs for stroke? Trends Neurosci.30, 433–439 (2007). ArticleCASPubMed Google Scholar
Russell, W. M. S. & Burch, R. L. The Principles of Humane Experimental Technique (Methuen, 1958). Google Scholar
Kilkenny, C., Browne, W. J., Cuthill, I. C., Emerson, M. & Altman, D. G. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol.8, e1000412 (2010). ArticleCASPubMedPubMed Central Google Scholar
Bassler, D., Montori, V. M., Briel, M., Glasziou, P. & Guyatt, G. Early stopping of randomized clinical trials for overt efficacy is problematic. J. Clin. Epidemiol.61, 241–246 (2008). ArticlePubMed Google Scholar
Montori, V. M. et al. Randomized trials stopped early for benefit: a systematic review. JAMA294, 2203–2209 (2005). ArticleCASPubMed Google Scholar
Berger, J. O. & Wolpert, R. L. The Likelihood Principle: A Review, Generalizations, and Statistical Implications (ed. Gupta, S. S.) (Institute of Mathematical Sciences, 1998). Google Scholar
Vesterinen, H. M. et al. Systematic survey of the design, statistical analysis, and reporting of studies published in the 2008 volume of the Journal of Cerebral Blood Flow and Metabolism. J. Cereb. Blood Flow Metab.31, 1064–1072 (2011). ArticlePubMed Google Scholar
Smith, R. A., Levine, T. R., Lachlan, K. A. & Fediuk, T. A. The high cost of complexity in experimental design and data analysis: type I and type II error rates in multiway ANOVA. Hum. Comm. Res.28, 515–530 (2002). Article Google Scholar
Perel, P. et al. Comparison of treatment effects between animal experiments and clinical trials: systematic review. BMJ334, 197 (2007). ArticleCASPubMed Google Scholar
Nosek, B. A. & Bar-Anan, Y. Scientific utopia: I. Opening scientific communication. Psychol. Inquiry23, 217–243 (2012). Article Google Scholar
Open-Science-Collaboration. An open, large-scale, collaborative effort to estimate the reproducibility of psychological science. Perspect. Psychol. Sci.7, 657–660 (2012). This article describes the Reproducibility Project — an open, large-scale, collaborative effort to systematically examine the rate and predictors of reproducibility in psychological science. This will allow the empirical rate of replication to be estimated.
Simera, I. et al. Transparent and accurate reporting increases reliability, utility, and impact of your research: reporting guidelines and the EQUATOR Network. BMC Med.8, 24 (2010). ArticlePubMedPubMed Central Google Scholar
Ioannidis, J. P. The importance of potential studies that have not existed and registration of observational data sets. JAMA308, 575–576 (2012). ArticleCASPubMed Google Scholar
Alsheikh-Ali, A. A., Qureshi, W., Al-Mallah, M. H. & Ioannidis, J. P. Public availability of published research data in high-impact journals. PLoS ONE6, e24357 (2011). ArticleCASPubMedPubMed Central Google Scholar
Ioannidis, J. P. et al. Repeatability of published microarray gene expression analyses. Nature Genet.41, 149–155 (2009). ArticleCASPubMed Google Scholar
Chambers, C. D. Registered Reports: A new publishing initiative at Cortex. Cortex49, 609–610 (2013). ArticlePubMed Google Scholar
Ioannidis, J. P., Tarone, R. & McLaughlin, J. K. The false-positive to false-negative ratio in epidemiologic studies. Epidemiology22, 450–456 (2011). ArticlePubMed Google Scholar
Siontis, K. C., Patsopoulos, N. A. & Ioannidis, J. P. Replication of past candidate loci for common diseases and phenotypes in 100 genome-wide association studies. Eur. J. Hum. Genet.18, 832–837 (2010). ArticleCASPubMedPubMed Central Google Scholar
Ioannidis, J. P. & Trikalinos, T. A. Early extreme contradictory estimates may appear in published research: the Proteus phenomenon in molecular genetics research and randomized trials. J. Clin. Epidemiol.58, 543–549 (2005). ArticlePubMed Google Scholar
Ioannidis, J. Why science is not necessarily self-correcting. Perspect. Psychol. Sci.7, 645–654 (2012). ArticlePubMed Google Scholar
Zollner, S. & Pritchard, J. K. Overcoming the winner's curse: estimating penetrance parameters from case-control data. Am. J. Hum. Genet.80, 605–615 (2007). ArticleCASPubMedPubMed Central Google Scholar