BMJ. Rothwell PM. Gefitinib or carboplatinpaclitaxel in pulmonary adenocarcinoma. 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]. Ticagrelor vs. clopidogrel in patients with non-ST- 2009;52:51522. J Bras Pneumol. The Y-axis denotes the treatment effect, e.g. It is important to point out that a predictive biomarker (factor) could have either quantitative or qualitative interaction with treatment. Subgroup analysis in randomised controlled trials: importance, indications, and interpretation. When there is sufficient statistical evidence to indicate an interaction, it is important to state the treatment effects by subgroups and not use the overall average treatment effect on all patients to characterize the effect of treatment across all subgroups. PMID. It also highlights the pitfalls in conducting undisciplined subgroup analyses. See Ondra et al (2016) [22] for examples and reviews of confirmatory subgroup analysis in cancer clinical trials that test targeted agents and immunotherapy. So, how can we identify data which are the result of play of chance, but do not make us burst out laughing? By clicking Accept, you consent to the use of ALL the cookies. As a library, NLM provides access to scientific literature. One major concern is that few trials have sufficient statistical power to estimate a treatment effect reliably in multiple subgroups. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide, This PDF is available to Subscribers Only. He coordinates the Alfred ICUs education and simulation programmes and runs the units educationwebsite,INTENSIVE. the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in You are using a browser version with limited support for CSS. Chan AW. For the study of Lindholm et al., patients with and without revascularization procedures (PCI or CABG) during the first 10 days were analysed,4 illustrating consistent trends for a positive treatment effect in both sub-subgroups, without an interaction for the higher overall bleeding risk associated with ticagrelor. 2021;9:36072. and transmitted securely. male and female, young and elderly patients. by dr. Helmut Schuehlen. government site. Key components of our proposed approach include targeted literature searches and key informant interviews to identify the most important subpopulations a priori during topic scoping, a framework for assessing the credibility of subgroup analyses reported in studies, and structured investigation of sources of heterogeneity of intervention effects. Yusuf S, Wittes J, Probstfield J, Tyroler HA. When a large number of unplanned subgroup analyses are conducted, the treatment may spuriously appear to be effective in one or more subgroups. Bethesda, MD 20894, Web Policies During the development of the statistical analysis plan of this work VC: Advisory board member: Alcon, Roche, Bayer, Novartis; Grants: Bayer, Novartisunrelated to this study. CAS Subdividing the cohort into groups can provide additional research information. PS was responsible for writing and critical review on manuscript. doi: 10.1161/JAHA.122.026173. examine outcomes in relation to intent of revascularization defined prior ", FESC, FACC, Vivantes Auguste-Viktoria-Klinikum Berlin, "In response to the editorial comment ""Pre-specified vs. post-hoc subgroup analyses: are we wiser before or after a trial has been performed?"" The term "empirical" is defined as treatment given prior to obtaining susceptibility results of microbial analysis. 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. Teprotumumab for patients with active thyroid eye disease: a pooled data analysis, subgroup analyses, and off-treatment follow-up results from two randomised, double-masked, placebo-controlled, multicentre trials. Eur Heart J. Cmaj. Debate: Subgroup analyses in clinical trialsfun to look at, but don't believe them! On Enrichment Strategies for Biomarker Stratified Clinical Trials. Intensive Care Med. In RCTs, subgroups are often defined by demographic variables, such as age, sex and race. Ou F, Le-Rademacher JG, Ballman KV, Adjei AA, & Mandrekar SJ (2020). A table or figure reporting about a dozen subgroup analyses is a near ubiquitous feature of major clinical trial publications. for several reasons: With a 30-day landmark we miss many early events that 2023 American Medical Association. Apparently compelling subgroup effects often prove spurious, and guidance is needed to differentiate credible from less credible subgroup claims. Dmitrienko A, Muysers C, Fritsch A, & Lipkovich I (2016). Apparently compelling subgroup effects often prove spurious, and guidance is needed to differentiate credible from less credible subgroup claims. An official website of the United States government. You also have the option to opt-out of these cookies. Brand KJ, Hapfelmeier A, Haller B. Customize your JAMA Network experience by selecting one or more topics from the list below. This article reviews key statistical concepts associated with planning, conducting, and interpreting subgroup analyses in RCTs. Subgroup analyses are either planned a priori before randomisation or they emerge after randomisation (post-hoc) [ 4 ]. The site is secure. Advertisement cookies are used to provide visitors with relevant ads and marketing campaigns. This would indicate stability of a treatment effect over a broad study population. PLATelet inhibition and patient Outcomes (PLATO) trial. Using network meta-analyses, we aim to investigate which SMT "application procedures" have . Was there any indirect evidence to support the apparent subgroup effectfor example, biological rationale, laboratory tests, animal studies? However, these reviews fail to consider that clinical effects may depend on SMT "application procedures" (i.e., how and where SMT is applied). However, the lack of stratified randomization does not a priori render subgroup analyses invalid. Pre-specified hypotheses of confirmatory subgroup analysis are based on strong biological evidence. In a recent investigation of published study protocols, a majority of cardiovascular trials reported specific articles on subgroup analyses, but only about 20% of these analyses were performed on a prespecified subgroup [ 13 ]. advocated a priori specification of subgroup hypotheses, completion of a small number of subgroup analyses, and use of an interaction test for analysing subgroup effects. For RCTs designed to evaluate the effect of an experimental treatment in the overall patient population, statistical tests to detect a treatment-by-subgroup interaction are often under-powered. randomization, both analyses are limited due to post-randomization 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. the differences in the treatment effects among various subgroups. Adolescent Psychological Assets and Cardiometabolic Health Maintenance in Adulthood: Implications for Health Equity. This distinguishes the design of PLATO from that of TRITON-TIMI 38, the trial on prasugrel in acute coronary syndromes,2 where only patients who had been scheduled for PCI were randomized. Cook DI, Gebski VJ, Keech AC. 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]. We decided to perform the analysis with the cut-point of 10 days Guidelines for Statistical Reporting in Medical Journals. To compensate, the size of the trial would have to be increased accordingly which is seldom done. Tutorial in Biostatistics: Data-driven subgroup identification and analysis in clinical trials, The cost of dichotomising continuous variables. Current guidelines do not recommend routine invasive treatment in all NSTEMI patients,11 supporting this focus on NSTEMI. The publisher's final edited version of this article is available free at, Statistical principles for clinical trials (ICH E9): an introductory note on an international guideline, Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Products, Guideline on the investigation of subgroups in confirmatory clinical trials. 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. Ginseng appears to have neutral . Any cookies that may not be particularly necessary for the website to function and is used specifically to collect user personal data via analytics, ads, other embedded contents are termed as non-necessary cookies. Lipkovich I, Dmitrienko A, DAgostino RB (2017). 8600 Rockville Pike width: auto; SJG: Consultant: Allergan, Apellis, Bausch and Lomb, Boehringer Ingelheim, Johnson and Johnson, Kanaph; Research funds: American Academy of Ophthalmology, Apellis, Boehringer Ingelheim, NGM Bio, Regeneronunrelated to this study. Murad MH, Montori VM, Ioannidis JP, Jaeschke R, Devereaux PJ, Prasad K, Neumann I, Carrasco-Labra A, Agoritsas T, Hatala R, Meade MO, Wyer P, Cook DJ, Guyatt G. JAMA. For permissions please email: journals.permissions@oup.com. The technique is widely used in medical research; The price tag that comes with any . 2004;180:28991. Sun X, Ioannidis JPA, Agoritsas T, Alba AC, Guyatt G. How to Use a Subgroup Analysis: Users Guide to the Medical Literature. Is a subgroup claim believable? Farrokhyar, F., Skorzewski, P., Phillips, M.R. in order to answer a relevant question that clinicians ask when discussing An a priori subgroup analysis by presence (or absence) and type of initial antimicrobial therapy is planned for the following categories: according to presence (or absence), with initial antimicrobial therapy and without . Long-term cardiometabolic health in people born after assisted reproductive technology: a multi-cohort analysis. (2019). More information on meta-analysis can be found in Higgins et al (2019) [12]. before any analyses were performed) the author group had thorough 2011 Feb 2;93(3):e8. of the hospitalization period, which we found to be clinically more 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. Understanding of interaction (subgroup) analysis in clinical trials Milos Brankovic, Milos Brankovic orcid.org/0000-0002-3996-0813 Clinical Epidemiology Unit, Department of Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands School of Medicine, University of Belgrade, Belgrade, Serbia Search for more papers by this author The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). https://doi.org/10.1038/s41433-022-01948-0, DOI: https://doi.org/10.1038/s41433-022-01948-0. 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. For the validity of the intended analysis and the data, the Maya J, et al. Accessibility Statement, Our website uses cookies to enhance your experience. About one fifth of those planned for 2020;19:391401. Usage. Data on the elderly are of common interest. Evidence-based surgery relies on the results of randomised controlled trials (RCTs). While we agree that these analyses are hypothesis generating due to font: 14px Helvetica, Arial, sans-serif; In order Interaction revisited: the difference between two estimates. ISSN 1476-5454 (online) definition of the subgroup. For full access to this pdf, sign in to an existing account, or purchase an annual subscription. Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. Updating criteria to evaluate the credibility of subgroup analyses. When reported, this information can often be found in the methods section of the article. pool.groups: Pool the results of two treatment arms; power.analysis: A priori power calculator; power.analysis.subgroup: A priori power calculator for subgroup contrasts Internet Explorer). font-weight: normal; Oxman AD, Guyatt GH. For example, the 21-gene recurrence score is associated with recurrence in tamoxifen-treated patients with node-negative, estrogen receptor (ER)positive breast cancer [9]. results, suggesting some robustness to the analyses. Ann Surg. 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. during the initial 10 days; and this time-point is also closer to the end Efficacy of Omega-3 Fatty Acid Supplementation for Treatment of Dry Eye Disease: A Meta-Analysis of Randomized Clinical Trials. 2010;251:40916. A pooled analysis of two RCTs of 107 patients with highly relapsing neuromyelitis optica spectrum disorder [18] illustrates effective adherence to these principles in its design. Reviews of these more flexible methods, such as the fallback procedure [15] and MaST procedure [16], can be found in Matsui et al (2014) [17] and Dmitrienko et al (2017) [18]. information on their rationale for choosing a post-hoc definition for this A users guide to subgroup analyses in the surgical literature. Differences between the two trials in design as well as results have spurred intensive discussions and debates. The p-value for interaction is rarely reported in the ophthalmology literature, making the independence of subgroup effects uncertain [8, 16]. BMJ. The result is more credible when the claim meets the following: Chris is an Intensivist and ECMO specialist at theAlfred ICU in Melbourne. government site. Epub 2023 May 3. PS: Nothing to disclose. discussions about the discordance between the pre-specified cut point at background: #fff; PLoS Med. These cookies will be stored in your browser only with your consent. FF: Nothing to disclose. A graphical approach to sequentially rejective multiple test procedures, Comparison of statistical analysis plans in randomize-all phase Ill trials with a predictive biomarker. Analysis and interpretation of treatment effects in subgroups of patients in randomized clinical trials. sharing sensitive information, make sure youre on a federal to randomization. Out of these cookies, the cookies that are categorized as necessary are stored on your browser as they are essential for the working of basic functionalities of the website. 2023 Jan 17;12(2):e026173. Like most recent large randomized trials, the design and methods of PLATO have been described in a dedicated publication10 which specified an array of subgroup analyses of efficacy and safety variables. The Caution is necessary when defining subgroups by a data-driven approach. This pre-specified analysis has been reported center (UCR), Study Group, Association Between Visual Acuity and Fluid Compartments with Treat-and-Extend Intravitreal Aflibercept in Neovascular Age-Related Macular Degeneration: An ARIES Post Hoc Analysis, Research Methodology for the Ophthalmologist, Cancel Recent NI trials have performed a priori subgroup analyses using standard statistical tests for interaction, but there is increasing interest in more flexible machine . How can we identify more reliable subgroup analyses? of medical sciences, Cardiology; and Uppsala clinical research center (UCR), Uppsala Universit, Long-term risk of atrial fibrillation or flutter after transcatheter patent foramen ovale closure: a nationwide Danish study, Cationic proteins from eosinophils bind bone morphogenetic protein receptors promoting vascular calcification and atherogenesis, Dynamical improvement after rescue balloon angioplasty for pulmonary vein occlusion complicated with radiofrequency catheter ablation, Lower income, higher risk: disparities in treatments and outcomes of patients with acute myocardial infarction, COVID-19 vaccination-related myocarditis: a Korean nationwide study. ISSN 0950-222X (print), When to believe a subgroup analysis: revisiting the 11 criteria, https://doi.org/10.1038/s41433-022-01948-0, for the Retina Evidence Trials InterNational Alliance (R.E.T.I.N.A.) 2012 Mar 15;344:e1553. PMID: Rothwell PM. The practice of conducting multiple statistical tests on a large number of subgroups to find a subgroup with significant treatment effect runs the high risk of inflating the overall type I error rate. 2007 Jul;3(7):407-13. clear: left; Nat Clin Pract Rheumatol. Syed MA, Aiyegbusi OL, Marston E, Lord JM, Teare H, Calvert M. Geroscience. As illustrated in Figure 2, gefitinib (an EGFR inhibitor) was associated with significantly better progression-free survival (PFS) compared to control (carboplatin plus paclitaxel) in EGFR mutants, while gefitinib was associated with significantly worse PFS compared to control in EGFR wild types. A trial database is easily analysed for all these different cut-off values. #mergeRow-gdpr fieldset label { Common challenges with subgroup analyses include poor definitions, low statistical power, and inflated type I error due to multiple hypotheses testing. See Wang et al (2018) [21] for further discussion of strategies to optimize the power of treatment-by-subgroup interactions in biomarker-stratified clinical trials. One possible explanation was the predominant vegetarian diet and low intake of omega-3 fatty acids in India. The effect of a treatment may vary by baseline patient characteristics (e.g. Was the subgroup analysis one of a small number of subgroup hypotheses tested (5)? We also use third-party cookies that help us analyze and understand how you use this website. Uppsala University, Sweden. Sun X, Briel M, Walter SD, Guyatt GH. Finally, in trials with an overall negative result, subgroup analyses might identify patient subsets with a significant treatment effect. consistent regardless of management strategy and regardless of the cut- 2011 Mar 28;342:d1569. Systematic reviews and meta-analyses of observational studies. Figure 1 (B) shows an example of quantitative interaction where although the magnitude of the treatment effect differs between the two subgroups, they are in the same direction. } FOIA Was the subgroup effect consistent with evidence from previous related studies? One criticism of the gating approach is that one might miss the opportunity to identify a targeted subgroup of patients who may benefit from the new treatment based on prior preclinical or early clinical observations. This still does not eliminate selective publication of results that fit a hypothesis. Usage power.analysis.subgroup (TE1, TE2, seTE1, seTE2, sd1, sd2, var1, var2, two.tailed=TRUE) Arguments Details 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. Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, & Hiller W (2004). General guidance on exploratory and confirmatory subgroup analysis in late-stage clinical trials. Based on official recommendations, a priori definition of subgroup analyses should always include examined subgroup characteristics and cut-off values which should be reasoned with clinical evidence or concrete assumptions. HHS Vulnerability Disclosure, Help 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. MRP: Nothing to disclose. 8600 Rockville Pike sharing sensitive information, make sure youre on a federal It attempts to find and illustrate patterns within and between subgroups. An official website of the United States government. National Library of Medicine my editorial. Dijkman B, Kooistra B, Bhandari M. How to work with a subgroup analysis. 2008;5:e230. DS: Consultant: Amgen, Bayer, Genentech, Novartis, Optovue; Research funds: Amgen, Genentech, Heidelberg, Optovue, Regeneron, Topconunrelated to this study. Recent NI trials have performed a priori subgroup analyses using standard statistical tests for interaction, but there is increasing interest in more flexible machine . HHS Vulnerability Disclosure, Help Eye 36, 20752077 (2022). See Lipkovich et al (2017) [6] for a comprehensive review of data-driven methods to define subgroups using clinical trials data. particular subgroup analysis rather than the previously announced, pre- We use cookies on our website to give you the most relevant experience by remembering your preferences and repeat visits. Wang X, Zhou J, Wang T, & George SL (2018). Effect of important modifiers on harmful effects in evidence synthesis practice of adverse events were insufficiently investigated: an empirical investigation. Well-designed surgical RCTs adequately assess the effectiveness and safety of new surgical treatments in the overall population, but reliable analysis of treatment effects across subpopulations has been slow to adapt [1]. By continuing to use our site, or clicking "Continue," you are agreeing to our, To register for email alerts, access free PDF, and more, Get unlimited access and a printable PDF ($40.00), 2023 American Medical Association. This would indicate stability of a treatment effect over a broad study population. Thank you for visiting nature.com. J Biopharm Stat. All outcomes and planned subgroup analyses should thus be prespecified and described in the original trial registry. Advertisement intended for healthcare professionals, Vivantes Auguste-Viktoria-Klinikum, Klinik fr Innere Medizin Kardiologie, Diabetologie und konservative Intensivmedizin, Rubensstr. PubMedGoogle Scholar. General guidance on exploratory and confirmatory subgroup analysis in late-stage clinical trials. They may find out that certain subgroups respond better than others or that there are differences between men and women, for example. The greater the extent to which Ondra T, Dmitrienko A, Friede T, Graf A, Miller F, Stallard N, & Posch M (2016). contracts here. plot.sucra: Print, summary and plot methods for objects created using. Privacy Policy| These cookies track visitors across websites and collect information to provide customized ads. Bmj. Or is it 75, 80, or perhaps 85 years? Interaction 2: Compare effect sizes not P values. This category only includes cookies that ensures basic functionalities and security features of the website. First of all, subgroup analyses may demonstrate consistent results over various complementary subpopulations, e.g. }, #FOAMed Medical Education Resources byLITFLis licensed under aCreative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. carefully and accurately before the trial is undertaken. aDepartment of Biostatistics & Bioinformatics, Duke University, Durham, North Carolina, bDepartment of Surgery, Brigham and Womens Hospital, Boston, Massachusetts, cDepartment of Health Sciences Research, Mayo Clinic, Rochester, Minnesota. Bmj 2003;326:219. Subgroup treatment effect interactions identified post hoc must be . While power analysis does . Learn how your comment data is processed. Subgroup analysis in clinical trials. was, however, substantial crossover. PubMed Central DS was responsible for critical review and feedback on manuscript. The Bonferroni method addresses the issue of multiplicity by lowering the critical value (making it harder) to declare statistical significance and therefore controls the false positive rate to its specified level. Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada, Forough Farrokhyar,Mark R. Phillips,Lehana Thabane,Mohit Bhandari&Varun Chaudhary, Department of Surgery, McMaster University, Hamilton, ON, Canada, Forough Farrokhyar,Philip Skorzewski,Mohit Bhandari&Varun Chaudhary, Mid Atlantic Retina, The Retina Service of Wills Eye Hospital, Philadelphia, PA, USA, Retinal Disorders and Ophthalmic Genetics, Stein Eye Institute, University of California, Los Angeles, Los Angeles, CA, USA, Biostatistics Unit, St. Josephs Healthcare-Hamilton, Hamilton, ON, Canada, Retina Consultants of Texas (Retina Consultants of America), Houston, TX, USA, Blanton Eye Institute, Houston Methodist Hospital, Houston, TX, USA, NIHR Moorfields Biomedical Research Centre, Moorfields Eye Hospital, London, UK, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA, Department of Ophthalmology, Mayo Clinic, Rochester, MN, USA, Center for Ophthalmic Bioinformatics, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA, Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA, Department of Ophthalmology, University of Bonn, Bonn, Germany, Singapore Eye Research Institute, Singapore, Singapore, Singapore National Eye Centre, Duke-NUD Medical School, Singapore, Singapore, Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC, Australia, Department of Surgery, (Ophthalmology), The University of Melbourne, Melbourne, VIC, Australia, You can also search for this author in There are further issues, relating to adjustments for covariates, for multiple comparisons, the decrease of statistical power, etc. 1992 Jan 1;116(1):78-84. doi: 10.7326/0003-4819-116-1-78. A subgroup analysis of PLATO patients who underwent PCI has long been awaited, but has not been presented yet. Subgroup Analysis. These results, both from an In this example, EGFR mutation is a predictive biomarker for gefitinib in NSCLC.
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