Recent NI trials have performed a priori subgroup analyses using standard statistical tests for interaction, but there is increasing interest in more flexible machine . The Y-axis denotes the treatment effect, e.g. For the validity of the intended analysis and the data, the plot.sucra: Print, summary and plot methods for objects created using. Subgroup analysis in randomised controlled trials: importance, indications, and interpretation. Is a subgroup claim believable? Figure 1 (C) shows an example of qualitative interaction where the treatment effects are in opposite directions. Subgroup Analysis Advantages. Therefore, as requested by many clinicians, we decided to analyse the Was the subgroup effect consistent across related outcomes? These criteria will help clinicians deciding whether to use subgroup analyses to guide their patient care. In RCTs, subgroups are often defined by demographic variables, such as age, sex and race. Clipboard, Search History, and several other advanced features are temporarily unavailable. 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. Recent NI trials have performed a priori subgroup analyses using standard statistical tests for interaction, but there is increasing interest in more flexible machine . 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]. 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. Planning subgroups based on the current understanding of biological mechanisms by anticipating pathophysiological, genetic, or biological heterogeneity [3] is equally important. To increase power and precision, the treatment and scheduling effects were analysed between treatment and scheduling regimens (interactions P-value of 0.10 for non-inferiority hypothesis) rather than the effects of each drug by scheduling regimen type. Although knowing how well a new treatment works in patients with a specific biomarker or a specific combination of disease stage and histology are important for the patients and their clinicians to make informed treatment decisions, it is important to be cautious when interpreting the results of subgroup analyses. Kahaly GJ, Douglas RS, Holt RJ, Sile S, Smith TJ. 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. 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. Publishers note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. While power analysis does . 2011;364:1897908. Chan AW. This category only includes cookies that ensures basic functionalities and security features of the website. Epub 2023 May 3. It is important to point out that a predictive biomarker (factor) could have either quantitative or qualitative interaction with treatment. Was there any indirect evidence to support the apparent subgroup effectfor example, biological rationale, laboratory tests, animal studies? Equal allocation yields the highest power. Necessary cookies are absolutely essential for the website to function properly. (PDF) Reporting and interpretation of subgroup analyses in heart my editorial. 2019;38:56573. and transmitted securely. Varun Chaudhary. (2019). For example, are the subgroups plausible given what is known about the clinical, pharmacological, and biological mechanisms? 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. DS: Consultant: Amgen, Bayer, Genentech, Novartis, Optovue; Research funds: Amgen, Genentech, Heidelberg, Optovue, Regeneron, Topconunrelated to this study. Randomized clinical trials (RCTs) are conducted to assess the effect of an experimental treatment on outcomes of a target patient population. 2012;344:e1553. 2021;18:35160. #mc-embedded-subscribe-form .mc_fieldset { An example of pre-specified exploratory subgroup analysis is the differential treatment effect between EGFR-positive and EGFR-negative patients in the IPASS trial, achieved through testing the treatment-by-biomarker interaction [8]. A priori power calculator for subgroup contrasts power.analysis 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. 2. Nat Clin Pract Rheumatol. On Enrichment Strategies for Biomarker Stratified Clinical Trials. Apparently compelling subgroup effects often prove spurious, and guidance is needed to differentiate credible from less credible subgroup claims. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. 2008;5:e230. efficacy and safety standpoint, are also consistent with the overall trial The p-value for interaction is rarely reported in the ophthalmology literature, making the independence of subgroup effects uncertain [8, 16]. clear: left; Common challenges with subgroup analyses include poor definitions, low statistical power, and inflated type I error due to multiple hypotheses testing. Pain Physician. 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 Accessibility Statement, Our website uses cookies to enhance your experience. Additionally, the majority of the procedures were performed Cook DI, Gebski VJ, Keech AC. Targeted agents or immunotherapy, for example, are expected to be effective for patients with certain genetic mutations or protein/genetic overexpression levels due to their mechanism of action. Dmitrienko A, Millen B, & Lipkovich I (2017). 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. Provided by the Springer Nature SharedIt content-sharing initiative, Eye (Eye) 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.) previously, with results consistent with the overall PLATO trial. Alosh M, Huque MF, Bretz F, & DAgostino RB Sr (2017). How to use a subgroup analysis: users' guide to the medical - PubMed Pre-specified vs. post-hoc subgroup analyses: are we wiser before or } There are further issues, relating to adjustments for covariates, for multiple comparisons, the decrease of statistical power, etc. At the end of the trial, 64.3% had undergone PCI and 10.2% CABG. for a subgroup analysis to be of value, it should address a clinically Such data sets may be very consistent. When to believe a subgroup analysis: revisiting the 11 criteria A graphical approach to sequentially rejective multiple test procedures, Comparison of statistical analysis plans in randomize-all phase Ill trials with a predictive biomarker. PLATelet inhibition and patient Outcomes (PLATO) trial. He is also a Clinical Adjunct Associate Professor at Monash University. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. Customize your JAMA Network experience by selecting one or more topics from the list below. We therefore provide 5 criteria to use when assessing the validity of subgroup analyses: (1) Can chance explain the apparent subgroup effect; (2) Is the effect consistent across studies; (3) Was the subgroup hypothesis one of a small number of hypotheses developed a priori with direction specified; (4) Is there strong preexisting biological supp. and transmitted securely. Unauthorized use of these marks is strictly prohibited. HHS Vulnerability Disclosure, Help government site. In order The validity of a subgroup analysis largely depends on reporting all of the conducted subgroup analyses regardless of their statistical significance [1] as well as consistency of the treatment effect across closely related outcomes [9]. J Bras Pneumol. Other subgroup analyses included gender, age group, starting health status, and type of habitat. Advertisement cookies are used to provide visitors with relevant ads and marketing campaigns. He is one of the founders of theFOAMmovement (Free Open-Access Medical education) and is co-creator oflitfl.com,theRAGE podcast, theResuscitologycourse, and theSMACCconference. This would indicate stability of a treatment effect over a broad study population. Thank you for visiting nature.com. 2005 Jan 8-14;365(9454):176-86. The first 4 criteria are applicable to individual studies or systematic reviews, the last only to systematic reviews of multiple studies. He is on the Board of Directors for theIntensive Care Foundationand is a First Part Examiner for theCollege of Intensive Care Medicine. Subgroup Analysis LITFL CCC Research Elhakeem A, Taylor AE, Inskip HM, Huang JY, Mansell T, Rodrigues C, Asta F, Blaauwendraad SM, Hberg SE, Halliday J, Harskamp-van Ginkel MW, He JR, Jaddoe VWV, Lewis S, Maher GM, Manios Y, McCarthy FP, Reiss IKM, Rusconi F, Salika T, Tafflet M, Qiu X, svold BO, Burgner D, Chan JKY, Gagliardi L, Gaillard R, Heude B, Magnus MC, Moschonis G, Murray D, Nelson SM, Porta D, Saffery R, Barros H, Eriksson JG, Vrijkotte TGM, Lawlor DA. Post-hoc subgroup analyses, in contrast, are data driven and are considered exploratory or hypothesis generating. Tutorial in Biostatistics: Data-driven subgroup identification and analysis in clinical trials, The cost of dichotomising continuous variables. Methods: Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ. A treatment effect 1 indicates the treatment is as effective as the control; a treatment effect greater than 1 indicates the treatment is better than the control; and a treatment effect less than 1 indicates the treatment is worse than the control. Was the subgroup effect consistent with evidence from previous related studies? Dmitrienko A, Muysers C, Fritsch A, & Lipkovich I (2016). Ticagrelor vs. clopidogrel in patients with non-ST- Subgroup Analysis of Trials Is Rarely Easy (SATIRE): a study protocol Subgroup analysis and interpretation for phase 3 confirmatory trials In quantitative interaction, the size of the treatment effect varies across subgroups, but the treatment effects in different subgroups are in the same direction. Quality of reporting of key methodological items of randomized controlled trials in clinical ophthalmic journals. General guidance on exploratory and confirmatory subgroup analysis in late-stage clinical trials. Multiple subgroup analyses of the same data increase the risk of generating false positive findings. The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology. Meta-Analysis Of Antenatal Depression And Adverse Birth Outcomes In US Outcomes were identified through a priori subgroup analyses, and dose-responses were assessed for exercise intensity and exposure duration. Ophthalmic Epidemiol. He created the Critically Ill Airway course and teaches on numerous courses around the world. Clinical epidemiology and outcomes of ventilator-associated pneumonia A systematic review of subgroup analyses in randomised clinical trials elevation acute coronary syndrome with or without revascularization: Brand KJ, Hapfelmeier A, Haller B. For example, it is common in oncology to use age cutoffs of 40 years and 65 years to classify patients into age groups: <40 as adolescent and young adult, 40-65 as adult, and >65 as older adult. male and female, young and elderly patients. event rates. Ranibizumab and Bevacizumab for Treatment of Neovascular Age-related Macular Degeneration: Two-Year Results. PubMed has received grant support, honoraria, or fees from Astra-Zeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers-Squibb, Correvio, Daiichi-Sankyo, and Eli Lilly & Company. An official website of the United States government. BMJ. 2016;26:7198. These results, both from an The smaller the p-value of the interaction test, the stronger the subgroup effect. The research work was partially supported by P01CA142538 (XFW) and R01AG066883 (XFW), and P30CA15083 (Mayo Clinic Comprehensive Cancer Center Grant; JLR and SJM). border: none; Lipkovich I, Dmitrienko A, DAgostino RB (2017). More flexible multiple testing procedures have been proposed and they take the correlation and the testing order into account as well as allow recycling the significance level after rejecting a hypothesis to test the remaining hypotheses at increased significance levels. 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. This editorial highlights the 11 criteria as a general guide for clinician readers of evidence regarding its use in clinical settings, but researchers interested in systematic reviews and individual research planning could consider following ICEMAN [21] as a more comprehensive instrument. During the development of the statistical analysis plan of this work Bmj 1996;313:808. Treating individuals 2. 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? -7. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer, Clinical trial designs for predictive biomarker validation: theoretical considerations and practical challenges. 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. As a result of this debate, these data are now illustrated in the Supplementary material online. J Bone Joint Surg Am. Google Scholar. Subgroup analysis is research that focuses on one or more subgroups of the main data set. The effect of a treatment may vary by baseline patient characteristics (e.g. They may find out that certain subgroups respond better than others or that there are differences between men and women, for example. Performance cookies are used to understand and analyze the key performance indexes of the website which helps in delivering a better user experience for the visitors. Bethesda, MD 20894, Web Policies The former is credible if planned based on a prespecified hypothesis,. information on their rationale for choosing a post-hoc definition for this 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. CREDIBILITY OF A SUBGROUP ANALYSIS FINDING. } Internet Explorer). Accessibility Finally, in trials with an overall negative result, subgroup analyses might identify patient subsets with a significant treatment effect. conducted post hoc, are primarily hypothesis generating and should be Is a subgroup effect believable? Randomized controlled trials of surgical interventions. Meta-analysis evaluates the heterogeneity of treatment effects reported from multiple clinical studies and synthesizes the estimates of the treatment effects. That leads us back to Peter Sleight. effect of ticagrelor for invasive vs. non-invasive management is to If subgroups are defined by continuous variables, it is preferable to use well established or published cutoffs. One example of qualitative interaction is from the IPASS trial for non-small cell lung cancer (NSCLC) [8]. These cookies will be stored in your browser only with your consent. Subgroup analysis is a common technique used in medical research. Ou F, Le-Rademacher JG, Ballman KV, Adjei AA, & Mandrekar SJ (2020). 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. Dept. preference should have been to maintain the original pre-specified Yusuf S, Wittes J, Probstfield J, Tyroler HA. } The authors declare no conflict of interest. What is the best dose of nature and green exercise for As a service to our customers we are providing this early version of the manuscript. 2014 Jul;312(2):171-9. doi: 10.1001/jama.2014.5559. Findings from confirmatory subgroup analysis may be used in applications for regulatory approval of the new treatment in the subgroups. Oxman AD, Guyatt GH. Simultaneous subgroup analyses create multiplicity, inflating the defined nominal significance level (alpha) [10] which increases the likelihood of spurious and compelling results by chance alone [1]. 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]. PDF When to believe a subgroup analysis: revisiting the 11 criteria - Nature font-weight: normal; When extensive preliminary data are available, statistical methods can be used to identify optimal boundaries to define subgroups based on high-dimensional variables.
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