Rethinking traditional survival analysis: Modulated renewal analysis with competing risks regression

The authors reported no conflicts of interest.The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest. The authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest. We read with interest the article by Guariento and colleagues1Guariento A. Doulamis I.P. Staffa S.J. Gellis L. Oh N.A. Kido T. et al.Long-term outcomes of truncus arteriosus repair: a modulated renewal competing risks analysis.J Thorac Cardiovasc Surg. 2021; ([Epub ahead of print])Google Scholar regarding long-term outcomes of truncus arteriosus repair. In their study, the authors applied an innovative statistical methodology that they call “modulated renewal analysis with competing risks regression.” In contrast to traditional survival analysis, this methodology allows one to perform time-to-event analysis of repeated events within the same patient while accounting for mortality as a competing outcome via informative censoring. The methodology addresses an important statistical issue that is in fact common to various pathologies, ranging from tetralogy of Fallot2Van den Eynde J. Sá M.P.B.O. Vervoort D. Roever L. Meyns B. Budts W. et al.Pulmonary valve replacement in tetralogy of Fallot: an updated meta-analysis.Ann Thorac Surg. 2020; ([Epub ahead of print])Abstract Full Text Full Text PDF Scopus (8) Google Scholar to aortic valve degeneration.3Sá M.P.B.O. Van den Eynde J. Simonato M. Cavalcanti L.R.P. Doulamis I.P. Weixler V. et al.Valve-in-valve transcatheter aortic valve replacement versus redo surgical aortic valve replacement: an updated meta-analysis.JACC Cardiovasc Interv. 2021; 14: 211-220Crossref PubMed Scopus (40) Google Scholar Patients suffering from these pathologies often undergo a series of reoperations and adverse events, while traditional Kaplan–Meier curves only take into account the first event for each patient. Furthermore, patients who died early might carry an elevated risk had they continued to be followed. For instance, we encountered a similar issue when studying the literature about coronary artery disease in patients with HIV.4McCutcheon K. Triantafyllis A. Van den Eynde J. Oosterlinck W. Vachiat A. Tsabedze N. et al.Coronary revascularization in patients with HIV.Trends Cardiovasc Med. 2021; ([Epub ahead of print])Crossref Scopus (2) Google Scholar These patients often experience recurrent major adverse cardiovascular events following revascularization. Nonetheless, various studies failed to show any difference with regard to major adverse cardiovascular event–free survival between HIV-positive versus HIV-negative patients. In contrast, cumulative hazard estimates for recurrent acute coronary syndrome did show a significantly greater incidence in HIV-positive patients.5Boccara F. Mary-Krause M. Teiger E. Lang S. Lim P. Wahbi K. et al.Acute coronary syndrome in human immunodeficiency virus-infected patients: characteristics and 1 year prognosis.Eur Heart J. 2011; 32: 41-50Crossref PubMed Scopus (82) Google Scholar From the perspective of therapy, 2 goals can be pursued in these populations: (1) reducing the number of patients experiencing any events, and (2) reducing the number of recurrent events in patients who have already experienced an event. It seems that traditional Kaplan–Meier curves are restricting us from observing effects of the latter type. This is alarming, because one would be discouraged to find out that a certain therapy does not reduce the overall event rate in a population, while failing to recognize that this therapy in fact protects a subset of patients from an avalanche of events. Returning to Guariento and colleagues,1Guariento A. Doulamis I.P. Staffa S.J. Gellis L. Oh N.A. Kido T. et al.Long-term outcomes of truncus arteriosus repair: a modulated renewal competing risks analysis.J Thorac Cardiovasc Surg. 2021; ([Epub ahead of print])Google Scholar the use of cumulative hazard estimates rather than traditional event-free survival estimates is important to predict the risk of recurrent events in patients who already had one or more preceding events. As demonstrated by the authors, a shorter duration of the interval from previous reoperation was associated with increased hazard risk of subsequent reoperations. In other words, there might exist a subset of patients who are at elevated risk of being caught up in a series of events. Being able to timely identify these would allow for better prognostication, closer follow-up, and/or adjustment of therapy. In conclusion, developments in the statistical methodology urge to rethink survival analysis. While the Kaplan–Meier curve remains one of the most frequently used methods, blind worship should be discouraged, and other tools, including those that take repeated events into account, should always be considered when appropriate. Guariento and colleagues1Guariento A. Doulamis I.P. Staffa S.J. Gellis L. Oh N.A. Kido T. et al.Long-term outcomes of truncus arteriosus repair: a modulated renewal competing risks analysis.J Thorac Cardiovasc Surg. 2021; ([Epub ahead of print])Google Scholar are thus to be congratulated on their important contribution. Long-term outcomes of truncus arteriosus repair: A modulated renewal competing risks analysisThe Journal of Thoracic and Cardiovascular SurgeryVol. 163Issue 1PreviewIn this study, we sought to identify independent risk factors for mortality and reintervention after early surgical correction of truncus arteriosus using a novel statistical method. Full-Text PDF Reply: Cardiac surgeons as innovative researchersJTCVS OpenVol. 8PreviewThe aggregate effect of clinical research has a large impact on patient care. Clinical research is used to develop evidence-based protocols, draft society guidelines, and help develop best practice recommendations. Despite the importance in maintaining high-quality, accurate, and up-to-date research, it is not uncommon to see complex clinical questions answered with outdated statistical methodology. Although it may seem trivial, selecting the appropriate study design and statistical analysis is critically important for producing accurate results, and, ultimately, guiding clinical decision-making. Full-Text PDF Open AccessReply from authors: A new shared vision on survival analysis: Good news from BaltimoreJTCVS OpenVol. 8PreviewWe read with interest the letter from Van den Eynde and colleagues.1 We must admit that it is quite difficult to reply to such a beautiful explanation of the main concept of our article. Recently, an increasing number of groups have used competing risk regression analysis to determine the influence of competing events such as mortality. As mentioned in our study, the new model combines this approach with modulated renewal analysis. This combination allows control of competing events and estimates the cause-specific probability of the event of interest at a particular time while allowing for repeated events during follow-up. Full-Text PDF Open AccessReply: Using different statistical tools to see forests and treesJTCVS OpenVol. 8PreviewWe read with interest the commentary provided by Van den Eynde and colleagues1 regarding the article by Guariento and colleagues2 and their examination of outcomes with a modulated renewal analysis in a group of truncus arteriosus patients at Boston Children's Hospital. Van den Eynde and colleagues1 provide additional insight about the statistical question and answer the conundrum investigators face when analyzing complex clinical data. Their discussion of major adverse cardiac events in patients with HIV makes clear that reliance on Kaplan-Meier methods and the accompanying log-rank testing can result in clinical events being overlooked when only examining the time to a first event. Full-Text PDF Open Access

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