Ranibizumab and bevacizumab for neovascular age-related macular degeneration. Subgroup analysis is a common technique used in medical research. PMID: Study to Prospectively Evaluate Reamed Intramedullary Nails in Tibial Fractures (SPRINT) Investigators. JAMA. Pain Physician. 2012;344:e1553. laughed when they were presented with these results. Additionally, the majority of the procedures were performed
Article Clipboard, Search History, and several other advanced features are temporarily unavailable. This function performs an a priori power estimation for a test for subgroup differences within a meta-analysis. BMJ. Pivotal trials on antithrombotic regimens in coronary artery disease have been performed with huge patient cohorts; in CURE, 12 562 patients were randomized,1 TRITON-TIMI 38 included 13 608 patients,2 and PLATO 18 624 patients.3 Such databases provide an extraordinary opportunity to study a treatment effect in several subgroups of patients whichalthough subsetsstill consist of thousands of patients. J Bras Pneumol. In this example, EGFR mutation is a predictive biomarker for gefitinib in NSCLC. Data on the elderly are of common interest. Inclusion in an NLM database does not imply endorsement of, or agreement with, Cook DI, Gebski VJ, Keech AC. sound from a medical standpoint, the authors' decision and rationale to do
The former is credible if planned based on a prespecified hypothesis, if there is a justified direction of the overall and subgroup effect, and if there is appropriate statistical testing for the underlying hypothesis. Which data will end up in a publication? As expressed in the editorial
really only clinically important in patients with non ST-elevation ACS. Farrokhyar F, Karanicolas PJ, Thoma A, Simunovic M, Bhandari M, Devereaux PJ, et al. About one fifth of those planned for
When extensive preliminary data are available, statistical methods can be used to identify optimal boundaries to define subgroups based on high-dimensional variables. Maya J, et al. In such cases, the therapeutic implications are unchanged by the interaction. Helmut Schhlen, Pre-specified vs. post-hoc subgroup analyses: are we wiser before or after a trial has been performed?, European Heart Journal, Volume 35, Issue 31, 14 August 2014, Pages 20552057, https://doi.org/10.1093/eurheartj/ehu202. Eur Heart J. BMJ. Eligibility criteria for large trials are often broad to ensure the trial results can be generalized to a larger patient population. preference should have been to maintain the original pre-specified
Article PMC Since the included population in an RCT is not homogenous a priori, treatment effects might vary across different subgroups. Using the same definition of subgroup enables comparison of outcomes between similar subgroups across different studies/clinical trials. Lindholm D, Varenhorst C, Cannon CP, Harrington RA, Himmelmann A,
Thus, assessing treatment outcome heterogeneity across subgroups and identifying patient characteristics that may modify the effect of the intervention under investigation has become common practice [4]. J Bone Joint Surg Am. Bethesda, MD 20894, Web Policies What is the interest of the scientific community in performing subgroup analyses? } An alternative to sequential approach is the Bonferroni method where the type I error rate is split between the overall test and the subgroup-specific tests. Dmitrienko A, Muysers C, Fritsch A, Lipkovich I. Multiplicity considerations in subgroup analysis, Testing for Qualitative Interactions between Treatment Effects and Patient Subsets, A comparison of the power of two tests for qualitative interactions. median), or visualization with statistical graphs. It is mandatory to procure user consent prior to running these cookies on your website. (i.e. For instance, an RCT of 702 patients (Protocol V of the DRCR net) with diabetic macular oedema and good visual acuity (VA) was designed to assess the effect of initial management with aflibercept or laser photocoagulation on vision loss versus observation [8] but failed to find significant changes in VA from either treatment versus observation in the overall population or across the predefined subpopulations. ACS management and PLATO. Confirmatory subgroup analyses are intended to evaluate subgroup-specific treatment effects and require that the subgroup analyses be specified in the design of the trial. Although subgroups can be defined using continuous variables, the loss of power and efficiency from categorization of continuous variables should be considered when defining subgroups in this manner [7]. The https:// ensures that you are connecting to the plot.sucra: Print, summary and plot methods for objects created using. Ophthalmic Epidemiol. Dijkman B, Kooistra B, Bhandari M. How to work with a subgroup analysis. Usage. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. If there is no interaction between treatment and subgroup, the treatment effect is the same across subgroups, as in Figure 1 (A). 2021 Mar; 16(3): 375380. Was the subgroup variable a stratification factor at randomization? The effect of a treatment may vary by baseline patient characteristics (e.g. If subgroup effects are credible, we will present the outcomes separately for each subgroup.40 If serious heterogeneity remains, we will rate down our certainty in the effect estimate.41. Farrokhyar, F., Skorzewski, P., Phillips, M.R. This still does not eliminate selective publication of results that fit a hypothesis. Randomized controlled trials of surgical interventions. Subgroup analysis in clinical trials. Is that just the perfect line never to be missed in the limitations section of a manuscript, or should we be more cautious beyond this? power.analysis.subgroup . comment[2], we also agree that subgroup analyses, especially those
More discussion on prognostic and predictive biomarkers in cancer research can be found in Mandrekar and Sargent (2009) [10] and Ballman (2015) [11]. If the investigators are so inclined to the report of p-values, they should be adjusted for multiplicity to control familywise type I error rate or false discovery rate. Was the subgroup hypothesis specified a priori? Abstract Introduction: We hypothesized that sedation with dexmedetomidine (an alpha2 adrenoceptor agonist), as compared with lorazepam (a benzodiazepine), would provide greater improvements in clinical outcomes among septic patients than among non-septic patients. 2014 Jul;312(2):171-9. doi: 10.1001/jama.2014.5559. 10,17,25,27,40 A post hoc variation of cut-off values may produce biased results and increase the probability of false . This category only includes cookies that ensures basic functionalities and security features of the website. Epub 2022 Nov 17. These data from ISIS-2 have been the favourite example to warn us of dividing populations into multiple subgroups, yielding data which may be the result of statistical play of chance. National Library of Medicine Ranibizumab and Bevacizumab for Treatment of Neovascular Age-related Macular Degeneration: Two-Year Results. and transmitted securely. Credibility of claims of subgroup effects in randomised controlled trials: systematic review. 2022 Dec;44(6):2585-2609. doi: 10.1007/s11357-022-00690-5. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, & Nishiwaki Y (2009). These cookies track visitors across websites and collect information to provide customized ads. In this paper we will provide a detailed exploration of the key aspects of sensitivity analyses including: 1) what sensitivity analyses are, why they are needed, and how often they are used in practice; 2) the different types of sensitivity analyses that one can do, with examples from the literature; 3) some frequently asked questions about sens. Cmaj. relevant question. If there exist differential treatment effect across subgroups, two types of treatment-by-subgroup interaction have been described -- quantitative versus qualitative interaction. 2020 Jun 1;30(6):839-845. doi: 10.1093/icvts/ivaa042. Guidelines for Statistical Reporting in Medical Journals. Even in unsuccessful NI trials, subgroup analyses can yield important insights about the potential reasons for failure to demonstrate non-inferiority of the experimental therapy. There are further issues, relating to adjustments for covariates, for multiple comparisons, the decrease of statistical power, etc. For instance, a meta-analysis of 17 RCTs examining the effect of omega-3 fatty acid supplementation for the treatment of dry eye disease [20] reported a significant decrease in dry eye symptoms from daily omega-3 fatty acid supplementation with 96% heterogeneity. et al. Arguably, the consistency of the subgroup effects in subsequent well-designed trials provide stronger credibility. No, the design paper had announced analyses of patients with any revascularization within the initial 30 days, not differentiating the STEMI and NSTEMI population.8. analysis. However, the question is what is elderly? Differences between the two trials in design as well as results have spurred intensive discussions and debates. display: inline; The decision to conduct a subgroup analysis should depend biological justification or on evidence of treatment heterogeneity from existing preliminary data. For example, are the subgroups plausible given what is known about the clinical, pharmacological, and biological mechanisms? Additional factors that affect the validity and the reproducibility of subgroup analyses are missing data and measurement error associated with the variables for searching and defining subgroups. By clicking Accept, you consent to the use of ALL the cookies. Subgroup analysis in clinical trials. the differences in the treatment effects among various subgroups. Their credibility is compromised by the effect of intervention and lack of statistical power [7, 9]. Lancet. Brand KJ, Hapfelmeier A, Haller B. FF: Nothing to disclose. doi: 10.1161/JAHA.122.026173. Manchikanti L, Datta S, Smith HS, Hirsch JA. Ondra T, Dmitrienko A, Friede T, Graf A, Miller F, Stallard N, & Posch M (2016). This editorial refers to Ticagrelor vs. clopidogrel in patients with non-ST-elevation acute coronary syndrome with or without revascularization: results from the PLATO trial, by D. Lindholm et al., on page 2083. He is one of the founders of theFOAMmovement (Free Open-Access Medical education) and is co-creator oflitfl.com,theRAGE podcast, theResuscitologycourse, and theSMACCconference. That is, as the magnitude of treatment effect increases for a subgroup, the likelihood of a real subgroup difference rises. The study found that the improvements in aggregated proptosis and diplopia responses from teprotumumab intravenous infusions compared to placebo were large and consistent, both in the overall population and across several predefined subgroups. volume36,pages 20752077 (2022)Cite this article. VC: Advisory board member: Alcon, Roche, Bayer, Novartis; Grants: Bayer, Novartisunrelated to this study. elevation acute coronary syndrome with or without revascularization:
Using network meta-analyses, we aim to investigate which SMT "application procedures" have . Functional cookies help to perform certain functionalities like sharing the content of the website on social media platforms, collect feedbacks, and other third-party features. the contents by NLM or the National Institutes of Health. Lancet Neurol. Findings from confirmatory subgroup analysis may be used in applications for regulatory approval of the new treatment in the subgroups. ISIS-2 (Second International Study on Infarct Survival) Collaborative Group, Randomized trial of intravenous streptokinase, oral aspirin, both or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2, Statement: updated guidelines for reporting parallel group randomised trials, Analysis and interpretation of treatment effects in subgroups of patients in randomized trials, Credibility of claims of subgroup effect in randomized controlled trials: systematic review, Comparison of ticagrelor, the first reversible oral P2Y12 receptor antagonist, with clopidogrel in patients with acute coronary syndromes: rationale, design, and baseline characteristics of the PLATelet inhibition and patient Outcomes (PLATO) trial, ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation, Ticagrelor versus clopidogrel in patients with ST-elevation acute coronary syndromes intended for reperfusion with primary percutaneous coronary intervention: a Platelet Inhibition and Patient Outcomes (PLATO) Trial subgroup analysis. Wang X, Zhou J, Wang T, & George SL (2018). Yusuf S, Wittes J, Probstfield J, Tyroler HA. Lancet Diabetes Endocrinol. Careers. BMJ
Other prognostic or confounding variables of the outcomes can also be included in these models to adjust for their potential association with the outcomes of interest. Systematic reviews and meta-analyses of observational studies. margin-right: 10px; 2004 Mar 15;180(6):289-91. 2010 Mar 30;340:c117. for a subgroup analysis to be of value, it should address a clinically
The main advantage of subgroup analysis is that it allows researchers to test their hypotheses in more detail. font-weight: normal; General guidance on exploratory and confirmatory subgroup analysis in late-stage clinical trials. LT was responsible for critical review and feedback on manuscript. For the validity of the intended analysis and the data, the
MeSH Interpretation of such interactions is particularly difficult, as on one hand the subgroup finding Quality of reporting of key methodological items of randomized controlled trials in clinical ophthalmic journals. Exploratory subgroup analyses are often conducted either in a post-hoc manner or are pre-specified at the design stage but without sufficient power to formally test for subgroup-specific treatment effects.