priori subgroup analysis

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. 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. Unlike confirmatory subgroup analysis, exploratory subgroup analyses are intended to obtain preliminary evidence and to generate hypotheses for future investigation. This website uses cookies to improve your experience while you navigate through the website. in order to answer a relevant question that clinicians ask when discussing center (UCR), PMID: Guillemin F. Primer: the fallacy of subgroup analysis. Subgroup analysis in clinical trials. Article National Library of Medicine 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]. PubMed CREDIBILITY OF A SUBGROUP ANALYSIS FINDING. The former is credible if planned based on a prespecied hypothesis, if 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. Subgroup analyses which have been pre-specified before data are available would eliminate data selection, but not play of chance. 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. Lai TY, Wong VW, Lam RF, Cheng AC, Lam DS, Leung GM. For example, the chance of making at least one false positive claim for conducting 10 repeated tests at 5% significance level is 40% when there is no treatment effect. VC: Advisory board member: Alcon, Roche, Bayer, Novartis; Grants: Bayer, Novartisunrelated to this study. How to Use a Subgroup Analysis - JAMA Network PLATelet inhibition and patient Outcomes (PLATO) trial. Absolute vs. relative effects-implications for subgroup analyses. All Rights Reserved. In the development of cancer targeted agents and immunotherapy, RCTs are conducted with an interest in demonstrating the treatment effect in all patients and/or in a targeted subgroup. This site uses Akismet to reduce spam. When to believe a subgroup analysis: revisiting the 11 criteria. 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. A priori power calculator for subgroup contrasts Description This function performs an a priori power estimation for a test for subgroup differences within a meta-analysis. Lagakos (2006) [23] and Wang et al (2007) [24] provide guidelines for presentation of subgroup analysis in medical journals. Updating criteria to evaluate the credibility of subgroup analyses. #mc-embedded-subscribe-form input[type=checkbox] { Effect of important modifiers on harmful effects in evidence synthesis practice of adverse events were insufficiently investigated: an empirical investigation. Was the test of interaction significant (interaction P < 0.05)? Although these explanations may appear by dr. Helmut Schuehlen. point selected for the landmark analyses. margin-top: 20px; Several systematic reviews and analyses have shown that authors report a difference in treatment effects between patient subgroups in 40-60% of all RCTs reporting subgroup analyses [10,40,59]. PS was responsible for writing and critical review on manuscript. However, they could also be quite divergent, with significant differences at one particular cut-off, perhaps non-significant trends at others, or results contradicting the main results. Subgroup analysis could also identify patient subsets with a particular treatment effect, either positive or negative. These criteria will help clinicians deciding whether to use subgroup analyses to guide their patient care. 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. These cookies will be stored in your browser only with your consent. 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. 2023 American Medical Association. The Year-2 CATT [15] assessing 2-year effects of the four original groups and the impact of switching from monthly scheduled to an as needed regimen found a similar gain in VA between treatment groups [1.4 letters difference; 95% CI 0.8, 3.7] but greater gain in the monthly scheduled regimen [2.4 letters difference; 95% CI 0.1, 4.8]. plot.subgroup.analysis.mixed.effects: Print, summary and plot methods for objects created using. HHS Vulnerability Disclosure, Help Conflicts of interest: H.S. We performed a priori subgroup analysis based on (1) subgroup of studies with mean left ventricular ejection fraction (LVEF) < 35%, (2) subgroup based on the timing of CA in relation to ICD shocks, and (3) subgroup based on the type of cardiomyopathy: whether study included patients with only ICM or ICM and NICM. Spinal manipulative therapy (SMT) is a guideline-recommended treatment option for spinal pain. Google Scholar. DS was responsible for critical review and feedback on manuscript. Lipkovich I, Dmitrienko A, DAgostino RB (2017). Accessibility The judicious design, analysis, and reporting of RCTs allow surgeons to effectively use the results in routine practice [1,2,3]. 1991 Jul 3;266(1):93-8. An approach to addressing subpopulation considerations in systematic One major concern is that few trials have sufficient statistical power to estimate a treatment effect reliably in multiple subgroups. comment[2], we also agree that subgroup analyses, especially those gender, age, and race), tumors molecular profile and genotype, and medical centers. . Optimising the selection of outcomes for healthy ageing trials: a mixed methods study. and JavaScript. The recommendation is based on multiple systematic reviews. All Rights Reserved, 2014;311(4):405-411. doi:10.1001/jama.2013.285063, Challenges in Clinical Electrocardiography, Clinical Implications of Basic Neuroscience, Health Care Economics, Insurance, Payment, Scientific Discovery and the Future of Medicine. Dmitrienko A, Millen B, & Lipkovich I (2017). 2005;365:17686. 2011;364:1897908. 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. Bmj 2010;340:c117. laughed when they were presented with these results. Therefore, failure to detect a significant interaction does not automatically imply the absence of treatment effect heterogeneity. 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]. 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. 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.) interpreted with caution. NSTE-ACS subgroup of the PLATO trial[1]. Safety and efficacy of tocilizumab versus azathioprine in highly relapsing neuromyelitis optica spectrum disorder (TANGO): an open-label, multicentre, randomised, phase 2 trial. The Author 2014. Sun X, Briel M, Walter SD, Guyatt GH. Disclaimer. Federal government websites often end in .gov or .mil. }, #FOAMed Medical Education Resources byLITFLis licensed under aCreative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Usage. 2023 Jan 17;12(2):e026173. First of all, subgroup analyses may demonstrate consistent results over various complementary subpopulations, e.g. Wang X, Zhou J, Wang T, & George SL (2018). Development of the Instrument to assess the Credibility of Effect Modification Analyses (ICEMAN) in randomized controlled trials and meta-analyses. of medical sciences, Cardiology; and Uppsala clinical research For instance, the CATT [14] conducted a non-inferiority trial to compare the efficacy of ranibizumab versus bevacizumab on either a monthly scheduled or an as needed regimen in patients with neovascular age-related macular degeneration and found equivalent gain in VA by treatment and dosing regimen at 1 year. So, the scientific community might postulate that all pre-specified subgroups need to be presented consecutively, at some point after the data are available for analyses. The At the end of the trial, 64.3% had undergone PCI and 10.2% CABG. Dmitrienko A, Muysers C, Fritsch A, & Lipkovich I (2016). the differences in the treatment effects among various subgroups. The magnitude and direction of the overall and subgroup effects are likely predictable if they are hypothesised based on a sound biological and clinical plausibility [7, 9]. 2014 Jul;312(2):171-9. doi: 10.1001/jama.2014.5559. Subgroup by treatment interaction assessments are routinely performed when analysing clinical trials and are particularly important for phase 3 trials where the results may affect regulatory labelling. Dijkman B, Kooistra B, Bhandari M. How to work with a subgroup analysis. Pre-specified subgroup analyses are more credible and valuable than post-hoc analyses. Lancet. Schandelmaier S, Briel M, Varadhan R, Schmid CH, Devasenapathy N, Hayward RA, et al. 2014;311(4):405411. PubMed Central You also have the option to opt-out of these cookies. To combat this, it is recommended to prespecify few highly relevant subgroups, use appropriate statistical tests to examine interactions between treatment effect and subgroup variables, and ensure p-values are adjusted for multiple testing [1, 7, 11]. Martin DF, Maguire MG, Fine SL, Ying GS, Jaffe GJ, Grunwald JE, et al. Methods for identification and confirmation of targeted subgroups in clinical trials: a systematic review, The challenge of subgroup analysesreporting without distorting. 2016;26:7198. The site is secure. For a test of treatment-by-biomarker interaction with equal numbers of subjects in all subgroups, the interaction test will have roughly four times the variance of an overall treatment effect. J Biopharm Stat. The effectiveness of spinal manipulative therapy procedures for spine Subgroup analysis is a common technique used in medical research. Is a subgroup effect believable? James S, Roe MT, Cannon CP, Cornel JH, Horrow J, Husted S, et al. Interact Cardiovasc Thorac Surg. This will "Re:In response to the editorial comment ""Pre-specified vs. post-hoc subgroup analyses: are we wiser before or after a trial has been performed?"" font: 14px Helvetica, Arial, sans-serif; The result is more credible when the claim meets the following: Chris is an Intensivist and ECMO specialist at theAlfred ICU in Melbourne. https://doi.org/10.1038/s41433-022-01948-0, DOI: https://doi.org/10.1038/s41433-022-01948-0. event rates. He is a co-founder of theAustralia and New Zealand Clinician Educator Network(ANZCEN) and is the Lead for theANZCEN Clinician Educator Incubatorprogramme. 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 support; and (5) Is the evidence supporting the effect based on within- or between-study comparisons. -7. 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. If there exist differential treatment effect across subgroups, two types of treatment-by-subgroup interaction have been described -- quantitative versus qualitative interaction. 2017;43:162. Evidence-based Urology: Subgroup Analysis in Randomized } 3. Rothwell PM. His one great achievement is being the father of three amazing children. But opting out of some of these cookies may have an effect on your browsing experience. Subgroup analysis: What it is + How to avoid mistakes Such a subanalysis of the non-ST-segment elevation myocardial infarction ( NSTEMI) population in PLATO (a subgroup by itself) has now been published, differentiating patients with or without revascularization.4. The longer the time period The greater the extent to which carefully and accurately before the trial is undertaken. Systematic reviews and meta-analyses of observational studies. Sun X, Briel M, Walter SD, Guyatt GH. We thank dr. Schuehlen for the interest in the article regarding the results, suggesting some robustness to the analyses. This function performs an a priori power estimation for a test for subgroup differences within a meta-analysis. 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. 2009;52:51522. Tutorial on statistical considerations on subgroup analysis in confirmatory clinical trials. Understanding of interaction (subgroup) analysis in clinical trials Address for correspondence: Xiaofei Wang, Department of Bioinformatics & Bioinformatics, Duke University, 2424 Erwin Road, Durham, NC 27710. All rights reserved. 2007;14:3908. An official website of the United States government. Was the subgroup variable a stratification factor at randomization? 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. 1992 Jan 1;116(1):78-84. doi: 10.7326/0003-4819-116-1-78. It also highlights the pitfalls in conducting undisciplined subgroup analyses. 2007 Jul;3(7):407-13. 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. Wasn't Peter Sleight a bit too harsh warning us that subgroup analyses are fun to look at, but don't believe them!?5 Let us look at the elderly. Subdividing the cohort into groups can provide additional research information. All outcomes and planned subgroup analyses should thus be prespecified and described in the original trial registry. Epub 2022 Nov 17. SJG was responsible for critical review and feedback on manuscript. Here, we revisit the 11 criteria (Table1) introduced by Sun et al. The main advantage of subgroup analysis is that it allows researchers to test their hypotheses in more detail. Bias, spin, and misreporting: time for full access to trial protocols and results. (PDF) Reporting and interpretation of subgroup analyses in heart 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 In general, when a specified level of overall type I error rate is allocated to testing multiple hypotheses with respect to different patient subgroups or endpoints and each test is conducted at its allocated significance level, the overall type I error rate will not exceed its specified level regardless if these tests are dependent or not. We also use third-party cookies that help us analyze and understand how you use this website. Was the subgroup analysis one of a small number of subgroup hypotheses tested (5)? These results, both from an 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. Findings from confirmatory subgroup analysis may be used in applications for regulatory approval of the new treatment in the subgroups. For the validity of the intended analysis and the data, the Clinical epidemiology and outcomes of ventilator-associated pneumonia Subgroup analysis involves assessing an association between an intervention (or other factor) and a subset of the patients that were exposed Subgroup analysis can be decided upon a priori or performed post hoc OBSERVATIONAL STUDIES However, the lack of stratified randomization does not a priori render subgroup analyses invalid. Brand KJ, Hapfelmeier A, Haller B. They usually present confidence intervals around the point estimate of subgroup treatment effect and the size of the symbols used is proportional to the size of subgroups. Subgroup Analysis LITFL CCC Research This site needs JavaScript to work properly. Intensive Care Med. General guidance on exploratory and confirmatory subgroup analysis in late-stage clinical trials. While we agree that these analyses are hypothesis generating due to In RCTs, subgroups are often defined by demographic variables, such as age, sex and race. This would indicate stability of a treatment effect over a broad study population. DL: institutional research grants and lecture fees from AstraZeneca. FF: Nothing to disclose. Therefore, I vividly encourage trialists to design subgroup analyses Advertisement intended for healthcare professionals, Vivantes Auguste-Viktoria-Klinikum, Klinik fr Innere Medizin Kardiologie, Diabetologie und konservative Intensivmedizin, Rubensstr. One possible explanation was the predominant vegetarian diet and low intake of omega-3 fatty acids in India. Giannaccare G, Pellegrini M, Sebastiani S, Bernabei F, Roda M, Taroni L, et al. Comparison of Confirmatory versus Exploratory Subgroup Analyses. HHS Vulnerability Disclosure, Help [7] and provide literature case examples to illustrate important principles and concepts in the interpretation of a subgroup analysis and to guide researchers in deciding their credibility in the ophthalmological literature. The treatment effect estimates and standard errors used to create the forest plot should not be derived from fitting separate models for the subgroups, but from a model on the full set of data, also including the interaction term between the treatment and the subgroup variable if interaction is significant. The effect of a treatment may vary by baseline patient characteristics (e.g. The site is secure. 2009 Sep-Oct;12(5):819-50. Using the same definition of subgroup enables comparison of outcomes between similar subgroups across different studies/clinical trials. 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 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. A simple gating approach is to sequentially test for the overall treatment effect before evaluating the effect within subgroups and once the null hypothesis of the overall treatment effect fails to be rejected, no subgroup analysis should be conducted. median), or visualization with statistical graphs. Cook DI, Gebski VJ, Keech AC. the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in He created the Critically Ill Airway course and teaches on numerous courses around the world. Figure 1 (C) shows an example of qualitative interaction where the treatment effects are in opposite directions. male and female, young and elderly patients. The statistical term to describe differential treatment effects by subgroups is the interaction between the treatment and the subgroup variable. really only clinically important in patients with non ST-elevation ACS. The difference did not exceed the non-inferiority margin of 5 letters. The p-value for interaction is rarely reported in the ophthalmology literature, making the independence of subgroup effects uncertain [8, 16]. 1. BMJ. FOIA 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 . Was the subgroup effect consistent across related outcomes? The .gov means its official. 2012;344:e1553. 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. In case of sale of your personal information, you may opt out by using the link. 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. Ophthalmic Epidemiol. While the first two approaches are performed frequently, the third is considered inappropriate by the scientific community. Ranibizumab and Bevacizumab for Treatment of Neovascular Age-related Macular Degeneration: Two-Year Results. Treating individuals 2. JAMA. In such cases, the therapeutic implications are unchanged by the interaction. More information on meta-analysis can be found in Higgins et al (2019) [12]. doi:10.1001/jama.2013.285063. 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]. to randomization. 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. Reporting of treatment effects on subgroups of patients are common in the medical literature. This pre-specified analysis has been reported Multiple subgroup analyses of the same data increase the risk of generating false positive findings. There are further issues, relating to adjustments for covariates, for multiple comparisons, the decrease of statistical power, etc. Given differences in the administration of surgical treatments and extent of biological variability, the interaction between treatment effect and various patient variables should be interpreted with caution [1]. Methods: Undefined cookies are those that are being analyzed and have not been classified into a category as yet. Subgroup analysis in randomised controlled trials: importance, indications, and interpretation. General guidance on exploratory and confirmatory subgroup analysis in late-stage clinical trials. power.analysis : A priori power calculator 2019;38:56573. In qualitative interactions, the treatment benefit is in favor of the experimental treatment in one subgroup but is unfavorable or neutral for the other subgroup. Careers. the contents by NLM or the National Institutes of Health.
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