PMID: Study to Prospectively Evaluate Reamed Intramedullary Nails in Tibial Fractures (SPRINT) Investigators. However, the lack of stratified randomization does not a priori render subgroup analyses invalid. Kahaly GJ, Douglas RS, Holt RJ, Sile S, Smith TJ. These criteria will help clinicians deciding whether to use subgroup analyses to guide their patient care. These circumstances carry important therapeutic consequences. 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. 1992;116:7884. Epub 2023 May 3. the time-point chosen ultimately did not affect the results much. Interaction 2: Compare effect sizes not P values. The p-value for interaction is rarely reported in the ophthalmology literature, making the independence of subgroup effects uncertain [8, 16]. 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]. 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. to randomization. 2010 Mar 30;340:c117. by dr. Helmut Schuehlen. 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. Subgroups can also be defined by variables that are prognostic of clinical outcomes and/or predictive of better treatment effect, such as disease severity, prior therapies, genotype, and biomarker status. 2016;26:7198. Development of the Instrument to assess the Credibility of Effect Modification Analyses (ICEMAN) in randomized controlled trials and meta-analyses. Publishers note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. efficacy and safety standpoint, are also consistent with the overall trial Gefitinib or carboplatinpaclitaxel in pulmonary adenocarcinoma. It is important to point out that a predictive biomarker (factor) could have either quantitative or qualitative interaction with treatment. In the original publication , the a priori power calculation based on the primary outcome postcardiotomy ventricular . This pre-specified analysis has been reported Varun Chaudhary. Uppsala University, Sweden. . With regard to the published article, it should be emphasized that The judicious design, analysis, and reporting of RCTs allow surgeons to effectively use the results in routine practice [1,2,3]. ), Industry funded randomised controlled trials, in the absence of statistically significant primary outcomes, are more likely to report subgroup analyses than non-industry funded trials, is one of a small number of hypotheses tested, is supported by the external evidence, and, subgroup analysisresults derived from a sound clinical trial are not necessarilyvalid, do not accept the validity ofsubgroup analysisresults without due consideration, subgroup analyses are generally considered hypothesis generating rather than practice changing. Clin Trials. Inclusion in an NLM database does not imply endorsement of, or agreement with, He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education. sharing sensitive information, make sure youre on a federal 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]. More information on meta-analysis can be found in Higgins et al (2019) [12]. Is it all patients over 65 years of age? intended for non-invasive management: substudy from prospective randomised Caution is necessary when defining subgroups by a data-driven approach. Updating criteria to evaluate the credibility of subgroup analyses. Undefined cookies are those that are being analyzed and have not been classified into a category as yet. 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. When reported, this information can often be found in the methods section of the article. DL: institutional research grants and lecture fees from AstraZeneca. The recommendation is based on multiple systematic reviews. 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. As a consequence, angiography during the index admission was performed in only 81.5%.3 Furthermore, only a subset of patients actually did undergo revascularization procedures. Brand KJ, Hapfelmeier A, Haller B. For full access to this pdf, sign in to an existing account, or purchase an annual subscription. and transmitted securely. Search for other works by this author on: The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) Trial Investigators, Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes ST-segment elevation, Prasugrel versus clopidogrel in patients with acute coronary syndromes, Ticagrelor versus clopidogrel in patients with acute coronary syndromes, Ticagrelor vs. clopidogrel in patients with non-ST-elevation acute coronary syndrome with or without revascularization: results from the PLATO trial. During the index admission, 61.0% of the overall population underwent percutaneous coronary intervention (PCI) and 4.5% underwent coronary artery bypass grafting (CABG). CREDIBILITY OF A SUBGROUP ANALYSIS FINDING. 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. Current guidelines do not recommend routine invasive treatment in all NSTEMI patients,11 supporting this focus on NSTEMI. Ann Intern Med. Google Scholar. plot.sucra: Print, summary and plot methods for objects created using. 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. PubMed Central Statistics notes. 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]. 2021;18:35160. Med J Aust. Would you like email updates of new search results? Lancet. JAMA. Trials. That leads us back to Peter Sleight. Effect of important modifiers on harmful effects in evidence synthesis practice of adverse events were insufficiently investigated: an empirical investigation. Conflicts of interest: H.S. 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. Eye 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. 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. Subdividing the cohort into groups can provide additional research information. the Hazard Ratio (HR) for Ctrl vs. Trt. Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ. Lai TY, Wong VW, Lam RF, Cheng AC, Lam DS, Leung GM. The difference did not exceed the non-inferiority margin of 5 letters. Post-hoc subgroup analyses, in contrast, are data driven and are considered exploratory or hypothesis generating. et al. The Author 2014. So, what would be the rationale to report on the NSTEMI population only? More discussion on prognostic and predictive biomarkers in cancer research can be found in Mandrekar and Sargent (2009) [10] and Ballman (2015) [11]. 2010;251:40916. Med J Aust. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. PLATelet inhibition and patient Outcomes (PLATO) trial. of medical sciences, Cardiology; and Uppsala clinical research Subgroup analysis is research that focuses on one or more subgroups of the main data set. A graphical approach to sequentially rejective multiple test procedures, Comparison of statistical analysis plans in randomize-all phase Ill trials with a predictive biomarker. Dmitrienko A, Muysers C, Fritsch A, Lipkovich I. James S, Roe MT, Cannon CP, Cornel JH, Horrow J, Husted S, et al. Pre-specified subgroup analyses are more credible and valuable than post-hoc analyses. Each of the monthly scheduled treatment groups were then rerandomized into monthly scheduled or as needed regimen. DS was responsible for critical review and feedback on manuscript. Lancet Neurol. clear: left; Subgroup analysis is a common technique used in medical research. They could indicate a differential treatment effect based on age, but could also be play of chance. 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. In the meantime, to ensure continued support, we are displaying the site without styles particular subgroup analysis rather than the previously announced, pre- The function implements the formulae described by Hedges and Pigott (2001). Spinal manipulative therapy (SMT) is a guideline-recommended treatment option for spinal pain. But was it pre-specified? Bmj 2003;326:219. volume36,pages 20752077 (2022)Cite this article. 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. 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]. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). background: #fff; 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. The site is secure. 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. Please enable it to take advantage of the complete set of features! Yusuf S, Wittes J, Probstfield J, Tyroler HA. 2012 Mar 15;344:e1553. Preference cookies are used to store user preferences to provide content that is customized and convenient for the users, like the language of the website or the location of the visitor. ", M.D., Dept. previously, with results consistent with the overall PLATO trial. doi: 10.1161/JAHA.122.026173. A statistical primer on subgroup analyses. strengthen their results and the validity of a publication, for the Ophthalmology 2020;127:S135s45. Types of treatment-by-subgroup interaction no interaction (A), quantitative interaction (B) and qualitative interaction (C). Tutorial in Biostatistics: Data-driven subgroup identification and analysis in clinical trials, The cost of dichotomising continuous variables. 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. National Library of Medicine 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. 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 Regardless of whether a subgroup analysis is specified a priori or post-hoc, investigators must consider inflated false positive rates, chance differences in observed treatment effects, low power for the comparisons of interest, and interpretation of the subgroup results. 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. Receive exclusive offers and updates from Oxford Academic, Autopsy Pathologist and CLIA Medical Director Leadership Opportunity University of Vermont Health Network, MEDICAL MICROBIOLOGY AND CLINICAL LABORATORY MEDICINE PHYSICIAN, CLINICAL CHEMISTRY LABORATORY MEDICINE PHYSICIAN, Copyright 2023 European Society of Cardiology. Interact Cardiovasc Thorac Surg. The authors declare no conflict of interest. my editorial. First of all, subgroup analyses may demonstrate consistent results over various complementary subpopulations, e.g. 2020;192:E901e6. Computing a priori power for planned subgroup analysis can allow reviewers to understand the potential power of their analyses and help inform whether a subgroup analysis is warranted given the number of eligible studies. for a subgroup analysis to be of value, it should address a clinically The site is secure. Bias, spin, and misreporting: time for full access to trial protocols and results. At the end of the trial, 64.3% had undergone PCI and 10.2% CABG. 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? Disclaimer. VC: Advisory board member: Alcon, Roche, Bayer, Novartis; Grants: Bayer, Novartisunrelated to this study. with non ST-elevation ACS to complement those published in the BMJ paper. really only clinically important in patients with non ST-elevation ACS. ", 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?"" As a result of this debate, these data are now illustrated in the Supplementary material online. This still does not eliminate selective publication of results that fit a hypothesis. To obtain Treating individuals 2. Subgroup analyses in clinical trials and observational studies have been discussed in regulatory agency guidelines [13] and comprehensive review of this topic have been published in applied statistical journals [45]. They may find out that certain subgroups respond better than others or that there are differences between men and women, for example. 2011 Feb 2;93(3):e8. was, however, substantial crossover. 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. 2023 American Medical Association. by dr. Helmut Schuehlen. contracts here. Subgroup effects are also more credible if the comparison was made within a study rather than across multiple studies with different methodological qualities [9]. When multiple variables are expected to contribute to the definition of a subgroup, a continuous prediction score calculated from a multivariable prediction model may be used to categorize patients into low, moderate or high risk, indicating an ordinal increase in the risk of an adverse outcome or the severity for a disease condition. You are using a browser version with limited support for CSS. Treatment effects could be quite different and side effects more frequent in older patients. Giannaccare G, Pellegrini M, Sebastiani S, Bernabei F, Roda M, Taroni L, et al. #mc-embedded-subscribe-form input[type=checkbox] { 2004;180:28991. Was the subgroup variable a baseline characteristic? Was the subgroup variable a stratification factor at randomization? 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. Absolute vs. relative effects-implications for subgroup analyses. 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. event rates. analysis. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives. The technique is widely used in medical research; The price tag that comes with any . (2019). 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. We will conduct a priori subgroup analyses, which were chosen by the parallel BMJ Rapid Recommendation panel (hypothesised direction of effect in parentheses): Credibility of claims of subgroup effects in randomised controlled trials: systematic review. 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. 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. Subgroup analysis in clinical trials. sharing sensitive information, make sure youre on a federal Bethesda, MD 20894, Web Policies Interpretation of such interactions is particularly difficult, as on one hand the subgroup finding from randomization, the larger potential for such time-dependent Cochrane handbook for systematic reviews of interventions, Forest plots and the interpretation of subgroups. 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 J Bras Pneumol. See Table 1 for a summary of the features of confirmatory and exploratory subgroup analysis. PMID: Rothwell PM. 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]. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. One example of qualitative interaction is from the IPASS trial for non-small cell lung cancer (NSCLC) [8]. See Ondra et al (2016) [22] for examples and reviews of confirmatory subgroup analysis in cancer clinical trials that test targeted agents and immunotherapy. Subgroup analysis in clinical trials. So, statisticians would caution us that these analyses are hypothesis generating at best, and cannot be regarded as evidence. Intensivist physician-to-patient ratios and mortality in the intensive care unit. 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.
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