H��S�/���o”��pO�rE��74 �,��}��������J� ��H9z�8�T��\ �C�����R�;{f��;����%H�4�1�� |J�� Apply the difference in restricted mean survival time (rmstD) in a NMA and compare the results with those obtained in a NMA with hazard ratio. This pooled treatment effect is a relative outcome measure often expressed for survival data as a pooled hazard ratio. One previous study highlighted the importance of the choice of a survival analysis model both in cost-effectiveness analyses (CEAs) alongside RCTs and for CEAs based on meta-analysis [30]. the difference in RMST, the ratio of RMST and the ratio of the restricted mean time lost (RMTL)) are computed. The difference in restricted mean survival times (RMSTs) up to a pre-specified time point is an alternative measure that offers a clinically meaningful interpretation. Then, one could use a pooled hazard ratio to derive the survival function in the experimental arm. Of note, two trials were each split into two separate comparisons which correspond to strata of these trials with patients receiving or not chemotherapy (PMCI 88C091 CT and PMCI 88C091; CHARTWEL CT and CHARTWEL). PLoS ONE 11(3): Calculate Mean Survival Time. Several regression-based methods exist to estimate an adjusted difference in RMSTs, but they digress from the model-free method of taking the area under the survival function. We applied Stewart and Parmar methodology [25] to estimate the pooled survival curve for the experimental arm using the pooled hazard ratio and the naive Kaplan-Meier survival curve in the control group. Performs two-sample comparisons using the restricted mean survival time (RMST) as a summary measure of the survival time distribution. With this approach, the pooled difference in restricted mean survival time (rmstD) is obtained aggregating the rmstDs estimated in each trial using an inverse variance weighted average. ¶Membership of the MAR-LC Collaborative Group is listed in the Acknowledgments. It provides a more easily understood measure of the treatment effect of an intervention in a controlled clinical trial with a time to event endpoint. it is the mean up to some point t ∗. With the first approach, the rmstD is estimated directly as the area between the two pooled survival curves. Except for the Naïve Kaplan-Meier method, all survival analysis methods were not available in standard statistical softwares. The rmstDs estimated using the different survival analysis methods are shown in Table 2. The aim of an IPD-MA is to estimate a pooled treatment effect from the aggregation of data from all randomised controlled trials (RCTs) that investigated the same clinical question [3–5]. The French data protection authority (CNIL – Commission Nationale de l'Informatique et des Libertés) strictly forbids us to make data collected during clinical trials freely available. Wrote the paper: BL AM JPP ORA JB. 274 0 obj <> endobj The MAR-LC comprised 2,000 distinct patients with a non-metastatic non-small cell lung cancer treated with radiotherapy and who had been enrolled in ten distinct phase III RCTs [19]. H��U]o�0�+�ў��N�im'���N�xmZ]:�n~=�v�vچ��Ǿ��sϽN�%�fpv6zW�+ u�}������8�������[�-�ʒ�Ќk(� Ǭgs9� @��pq��P�D�!S�Y$��� �c2 ���)sdR��Y�V��H�N���p��v�&�c����|"Ӛf�EA��������qŹ �f��0Q|n�@#�K���u����yO�K���U�v���*��{���?���MְCz�H� b�j�P�9C��f���9P���5�)�›gZ�!��5��t)�@�`˓���~)� GN��J�L���X��ֿ�M�aK3�D^D5�$_���CЯM*�@�� Some economic studies have already used IPD-MA [8–10]. Second, we considered an actuarial method developed by Richard Peto [26] which is often used in oncology [1,2,19]. Panel A of Fig. https://doi.org/10.1371/journal.pone.0150032.s001, https://doi.org/10.1371/journal.pone.0150032.s002, https://doi.org/10.1371/journal.pone.0150032.s003. Downloadable! The method applies the restricted mean (RM) for the estimation of ‘‘time’’ spent in a particular state of health. It is a two-stage method which is based on the estimation of the treatment effect, firstly, in each RCT and secondly, the aggregation of estimates [22–24]. Copyright: © 2016 Lueza et al. Modified RT is considered cost-effective if the ICER is less than the willingness-to-pay for one life year. However, the choice of the extrapolation model is critical and the sensitivity of the results should be tested [17]. We had access to the patient-level data from the Meta-Analysis of Radiotherapy in Lung Cancer (MAR-LC) collaborative group [19] which was previously used in a Dutch economic evaluation [20]. This case study showed that the choice of survival analysis method to estimate the difference in restricted mean survival time from an IPD meta-analysis is likely to exert an impact on cost-effectiveness results. At a ceiling ratio of € 25,000 per life year-gained, the probability of the experimental treatment being cost-effective ranged from 31% to 68%. Difference in Restricted Mean Survival Time for Cost-Effectiveness Analysis Using Individual Patient Data Meta-Analysis: Evidence from a Case Study By Béranger Lueza, Audrey Mauguen, Jean-Pierre Pignon, Oliver Rivero-Arias, Julia Bonastre and null null Gustave Roussy, Ligue Nationale Contre le Cancer meta-analysis plateform, Villejuif, France, Affiliations The funding sources had no role in study design, data collection, data analysis, data interpretation, or manuscript writing. https://doi.org/10.1371/journal.pone.0150032, Editor: Robert K. Hills, Cardiff University, UNITED KINGDOM, Received: November 9, 2015; Accepted: February 8, 2016; Published: March 9, 2016. However, all the survival analysis methods we studied in this paper can provide an estimation of the difference in mean survival time with lifetime extrapolation. This case study suggests that the method chosen to estimate the rmstD from IPD meta-analysis is likely to influence the results of cost-effectiveness analyses. The restricted mean is a measure of average survival from time 0 to a specified time point, and may be estimated as the area under the survival curve up to that point. Cost-effectiveness acceptability curves were derived from the 1,000 ICERs based on the bootstrap replicates to illustrate the uncertainty surrounding the cost-effectiveness of the experimental arm radiotherapy. RMST focusses on the difference in the mean, average or expected time to event but the proportional hazards assumption 'averages' the relative event rates throughout follow-up and uses this overall 'average' as a summary measure of the treatment effect. Belani (Penn State Hershey Cancer Institute), J. Beresford (Peter MacCallum Cancer Centre), J. Bishop (Victorian Comprehensive Cancer Centre), J.A. Yes If the true survival curves remain separated beyond the point of restriction, the difference in restricted means will increase with t *. 944 patients in the conventional radiotherapy arm and 1,046 in the modified radiotherapy arm. Restricted mean survival time is a well-established, yet underused, measure that can be interpreted as the mean event-free survival time up to a prespecified, clinically important point. Economic evaluations based on IPD-MA raise methodological concerns because of data clustering (patients within trials) which must be considered in the analysis. The RMST and RMTL options estimate the restricted mean survival time and the restricted mean time lost, respectively. Similarly, in the Pooled Exponential method, all observations (at any time) are used to fit the best model. No, Is the Subject Area "Radiation therapy" applicable to this article? Alternatively, similarly to the Stewart-Parmar method and to the method used in a number of studies reviewed by Guyot and colleagues [30], one could fit a parametric model to compute the survival function in the control arm. The results of the cost-effectiveness analysis were presented using the incremental cost-effectiveness ratios (ICER) expressed as the cost per life-year gained and cost-effectiveness acceptability curves [29]. The unit costs were extracted from the literature for medical transportation [27] and disease progression costs [28]. In order to estimate the rmstD from IPD-MA, we considered methods used by Wei and colleagues [18] and chose to adapt other non-parametric methods that are applied in the field of IPD-MA. It performs an ANCOVA-type covariate adjustment as well as unadjusted analyses for … For the second approach, with the Pooled Kaplan-Meier method, difference in mean survival time could be estimated for each trial using Kaplan-Meier curves with extrapolated parametric [33] or non-parametric [34] tails. Issues raised by the estimation of the rmstD for economic evaluation from a trial have already been investigated but none of these studies dealt with the use of IPD-MA [15–17]. The selection of the parametric model was based upon the log-likelihood ratio test and log-cumulative hazard plots [17]. endstream endobj 275 0 obj <>/Metadata 27 0 R/Pages 272 0 R/StructTreeRoot 71 0 R/Type/Catalog>> endobj 276 0 obj <>/MediaBox[0 0 595.32 841.92]/Parent 272 0 R/Resources<>/Font<>/ProcSet[/PDF/Text/ImageC]/XObject<>>>/Rotate 0/StructParents 0/Tabs/S/Type/Page>> endobj 277 0 obj <>stream %%EOF We are grateful to Jean Bouyer, Ariane Dunant, Matthieu Faron, Gwenael Le Teuff, Stefan Michiels and Federico Rotolo for scientific discussions and support. The RMST approach is applied to five completed CVOTs and is compared with the corresponding hazard ratios. Gustave Roussy, Service de biostatistique et d’épidémiologie, Villejuif, France, No, Is the Subject Area "Oncology" applicable to this article? 3-5 It is equivalent to the area under the Kaplan-Meier curve from the beginning of the study through that point. For the first approach, the rmstD can be estimated based on the follow-up of the trials using pooled survival curves. I came across this article which discusses some modifications to a traditional clinical trial monitoring setting where a time-to-event outcome is described in terms of the restricted mean survival time (RMST). No, Is the Subject Area "Survival analysis" applicable to this article? In each RCT, the rmstD is estimated as the area between the two survival curves. CHART: Continuous Hyperfractionated Accelerated Radiation Therapy; CHARTWEL: CHART Week-End Less; CI: confidence interval; CT: chemotherapy; ECOG: Eastern Cooperative Oncology Group; HR: Hazard ratio for Modified RT versus Conventional RT; MAR-LC: Meta-Analysis of Radiotherapy in Lung Cancer; NCCTG: North Central Cancer Treatment Group; PCMI: Peter MacCallum Institute; RTOG: Radiation Therapy Oncology Group; RT: Radiotherapy; *: see reference [19] for further details and for the trials references. PLOS ONE promises fair, rigorous peer review, The difference in restricted mean survival between PWID and people who did not inject drugs was − 0.19 years (95% CI: -0.29, − 0.09). The Pooled Kaplan-Meier method addresses non-proportional hazards, whereas the Pooled Exponential method, which is based on the exponential proportional hazards model, does not. For more information about PLOS Subject Areas, click This aggregation method ensures the correct comparisons of patients within each RCT (stratification by trial) and therefore an unbiased estimation of the pooled treatment effect. Three kinds of between-group constrast metrics (i.e. Based on two applications and a simulation study, the authors concluded that the three methods yielded similar results with respect to bias, mean square error and coverage probability. The restricted mean is a measure of average survival from time 0 to a specified time point, and may be estimated as the area under the survival … The rmstD is then the area between the two Kaplan-Meier survival curves. Funding: This work was supported by ITMO Cancer and IReSP (French Public Health Research Institute) as part of the French “Plan Cancer 2009–2013”, by the French “Programme Hospitalier de Recherche Clinique”, and by the French “Ligue Nationale Contre le Cancer”. Commonly to other case studies, our results were driven by the characteristics of our clinical data. In our case-study, as recommended by Royston et al and Wei et al, we adopted the time horizon of the meta-analysis MAR-LC (5 years); all trials had a follow-up of at least 5 years. Here, we describe the use of the restricted mean survival time as a possible alternative tool in the design and analysis of these trials. As a matter of fact, research on methods used to conduct economic evaluation based on IPD-MA is still in its infancy [11–14]. Survival curves for the two arms in MAR-LC estimated using Naive Kaplan-Meier and Stewart-Parmar, Peto-month, Peto-year and Peto-quintiles are respectively shown in S1–S4 Figs. Survival probabilities in each arm are estimated at predetermined time intervals from the pooled hazard ratio, which may vary between time periods, and from the survival probability of the whole population (both control and experimental arms). The rmstDs are then pooled across trials. Survival probabilities are estimated after each event in the naive Kaplan-Meier, Pooled Kaplan-Meier, and Stewart-Parmar methods. I describe the use of restricted mean survival time as an alternative outcome measure in time-to-event trials. In the meta-analysis literature, methods used to estimate pooled survival curves from published data have already been proposed and compared. Our aim was to study if/how the choice of a method … We did not consider the non-parametric pseudo-values method, but Wei et al. Modified RT was associated with longer overall survival (pooled hazard ratio = 0.88, 95% CI: [0.80–0.97], p = 0.009). In economic evaluation, a commonly used outcome measure for the treatment effect is the between-arm difference in restricted mean survival time (rmstD). Gustave Roussy, Service de biostatistique et d’épidémiologie, Villejuif, France, We used IPD from the Meta-Analysis of Radiotherapy in Lung Cancer concerning 2,000 patients with locally advanced non-small cell lung cancer, included in ten trials. This second approach is an extension of the inverse variance weighted average method that is classically used in meta-analysis to pool treatment effects across RCTs. Conversely, a common outcome measure in economic evaluation is the difference in the restricted mean survival time (rmstD) [6,7]. The restricted mean survival time (RMST), sometimes called the restricted mean event time, is an alternative measure that is more often reliably estimable than the mean and median of the event time in certain situations. The Naive Kaplan-Meier method considers the IPD from the different RCTs as if they originated from a unique RCT. In each trial, the mean cost per patient for RT and medical transportation were estimated from the number of RT fractions received. Mean survival time (MST), however, has received less attention in the field of clinical research, partly because it is often subject to underestimation due to the largest observation being censored. With this method, stratification by trial and treatment effect heterogeneity are addressed but the treatment effect is assumed to be constant over time (proportional hazards assumption). This method does not assume proportional hazards, but neither stratification by trial nor heterogeneity of treatment effect can be taken into account to estimate the pooled survival curves. The average incremental cost-effectiveness ratio (ICER) and acceptability curves were sensitive to the method used to estimate the rmstD. ENDPOINT. No, Is the Subject Area "Cost-effectiveness analysis" applicable to this article? The size of the square is directly proportional to the amount of information contributed by the trial. All these methods have never been applied to assess the rmstD for economic evaluation. We coded the methods using R version 3.1.3 (R Foundation, Vienna, Austria) and SAS version 9.3 (SAS Institute, Cary, NC). Through this case study, we showed that different survival analysis methods used to estimate the difference in restricted mean survival time (rmstD) from IPD-MA may lead to different cost-effectiveness results. They compared three methods of estimation of the trial-specific rmstD: the “Integrated difference of survival functions” method, which is equivalent to the Pooled Kaplan-Meier method, a pseudo values method and a flexible parametric survival model. Code is available from the authors upon request. With the second approach, we selected one parametric model as Wei et al [18]. Background: Restricted mean survival time (RMST) is an underutilized estimand in time-to-event analyses. Readers may contact the corresponding author at jean-pierre.pignon@gustaveroussy.fr to request the data. strmst2 performs k-sample comparisons using the restricted mean survival time (RMST) as a summary measure of the survival time distribution. Between-group comparisons were based on the estimated between-group differences in restricted mean survival times, with bootstrapped 95% CIs.12 In enhanced swimmer plots that complemented the TFS restricted mean time of each health state also was quan-tified as a percentage of the 36-month period. When different lengths of follow-up is an issue (e.g. Performed the experiments: BL AM JPP ORA JB. Conceived and designed the experiments: BL AM JPP ORA JB. It is estimated as the between-arm difference in the restricted mean survival time (rmstD) and corresponds to the area between the two survival curves for the experimental arm and the control arm restricted to a certain time horizon [7]. The Pooled Kaplan-Meier method and the Pooled Exponential method enable us to study the heterogeneity of the rmstDs across trials (Fig 1). RMST is the area under the Kaplan Meier survival curve. * E-mail: beranger.lueza@gustaveroussy.fr, Affiliations For more information about PLOS Subject Areas, click We chose the exponential model because log-likelihood ratio tests and log-cumulative hazard plots in each of the MAR-LC trials were in favour of this model. Schild (Mayo Clinic), A.T. Turrisi (Sinai Grace Hospital), A. Zajusz (Maria Sklodowska—Curie Memorial Cancer Center and Institute of Oncology). Therefore, an alternative approach known as the Restricted Mean Survival Time (RMST) or τ-year mean survival time is presented, and its ability to overcome interpretation challenges with the hazard ratio discussed. here. Stewart-Parmar and Peto methods are based on the aggregation of the hazard ratios across RCTs using the inverse variance weighted average. Three kinds of between-group contrast metrics (i.e., the difference in RMST, the ratio of RMST and the ratio of the restricted mean time lost (RMTL)) are computed. Yes So far, two non-parametric methods (Stewart-Parmar and Peto methods) have been used for estimating pooled survival curves from IPD meta-analysis [25,26]. First, it addresses stratification by trial, treatment effect heterogeneity, and non-proportionality of hazards. e0150032. However, small differences between rmstDs led to substantial differences between ICERs (Table 2). With the second approach, the rmstD is based on the aggregation of the rmstDs estimated in each trial. It can also account for a potential difference in the treatment effect between trials (between-trial heterogeneity). They ranged from 1.7 month in the Peto-quintiles method to 2.5 months in the Pooled Exponential method. Pooled Kaplan-Meier, Peto-month, naive Kaplan-Meier and Stewart-Parmar acceptability curves were similar whereas the acceptability curves based on the Peto-year and Peto-quintiles methods were notably lower than the others. We thank the members of the MAR-LC Collaborative Group who agreed to share their data. In this case-study, we illustrate how different survival analysis methods can be used to estimate the rmstD for economic evaluation using IPD-MA. Even though, there was no treatment effect heterogeneity between MAR-LC trials and survival hazards were proportional, we noted a difference in mean ICERs generated by the methods. Our aim was to study if/how the choice of a method impacts on cost-effectiveness results. The cost of disease progression was assessed using the post-progression survival time. The variable Cell is specified in the STRATA statement to compute the RMST for each type of cancer cell. This absolute outcome can be expressed as the number of life-years gained associated with the treatment. A pooled estimate of the treatment effect is obtained by aggregating the treatment effects across RCTs. h�b```�f�;B cB�I;'0�X�b9���8��ۀ�q��T����T�,�F� � 蚀f�0���fbn�љAH%0ؘψ*}!G>�� ä�����+$8dz�4�}ܿ@X )Y�0���@� ��$� Details on the methods are provided in Table 1 and in the S1 Supporting Information. Each trial is represented by a square, the center of which denotes the difference in restricted mean survival time (rmstD) for that trial comparison, with the horizontal lines showing the 95% CIs. endstream endobj startxref No, Is the Subject Area "Non-small cell lung cancer" applicable to this article? The overall proportional hazard assumption was verified in the meta-analysis (p = 0.91) as well as in individual trials according to Wei and colleagues’ approach [18]. Earle and Wells [32] compared five methods to combine published survival curves from studies of patients treated with chemotherapy for advanced non-small-cell lung cancer. Yes broad scope, and wide readership – a perfect fit for your research every time. University of Oxford, National Perinatal Epidemiology Unit, Nuffield Department of Population Health, Oxford, United Kingdom, Modified RT included hyperfractionated RT which consists in increasing the number of fractions per day with a decreased dose per fraction, and/or accelerated RT, in which the overall treatment time is reduced. Naive Kaplan-Meier and Stewart-Parmar provided the same survival curve, by definition, for the conventional arm, and quite similar survival curves for the modified arm (S1 Fig). This study illustrates how different survival analysis methods can be used to estimate the rmstD for economic evaluation using individual patient data (IPD) meta-analysis. No, PLOS is a nonprofit 501(c)(3) corporation, #C2354500, based in San Francisco, California, US, https://doi.org/10.1371/journal.pone.0150032. The mean total cost per patient was € 25,331 (95% CI: € 23,630–€ 27,115) for conventional RT and € 29,659 (95% CI: € 27,845–€ 31,507) for modified RT, corresponding to a mean incremental cost of € 4,328 (95% CI: € 1,830–€ 6,804). Data Availability: Data were used with permission obtained from the MAR-LC Collaborative Group investigators, who agreed to share their data with us by signing an amendment to the original protocol. The Pooled Kaplan-Meier and Pooled Exponential methods deal with stratification by trial and treatment effect heterogeneity. Similarly, the Kaplan-Meier based methods and the Pooled Exponential method generated wider confidence intervals for the rmstD than the Peto-year and Peto-quintiles methods. Furthermore, without PH, the estimated HR is not a simple average of HRs over time, and is even more difficult to interpret. 1,2 In this article, we discuss the advantages of an alternative analytical procedure based on the restricted mean survival time (RMST) 1,2 via 3 examples. Competing interests: The authors have declared that no competing interests exist. Click through the PLOS taxonomy to find articles in your field. Second, time interval definition used in each method also influences cost-effectiveness results. This study illustrates how different survival analysis methods can be used to estimate the rmstD for economic evaluation using individual patient data (IPD) meta-analysis. here. The restricted mean survival time is a robust and clinically interpretable summary measure of the survival time distribution. Mean ICERs ranged from € 24,299 to € 34,934 per life-year gained, respectively for the Pooled Exponential and the Peto-quintiles methods (Table 2). Gustave Roussy, Ligue Nationale Contre le Cancer meta-analysis plateform, Villejuif, France, Affiliations The method used in meta-analysis to pool treatment effects across RCTs is the inverse variance weighted average, also called fixed effect model [21]. You can get the restricted mean survival time with print(km, print.rmean=TRUE). There is thus a compromise to achieve between a too short time horizon that would not take into account all information from all trials, and a too long time horizon that would necessitate the use of parametric extrapolation (see below) for most of the trials in the meta-analysis. With the first approach, the rmstD is estimated directly as the area between the two pooled survival curves. Second, unlike the actuarial Peto method, it does not rely on any time interval definition. We estimated HRs and differences in restricted mean survival times, the mean difference in time alive and AF free. endstream endobj 278 0 obj <>stream The acceptability curve of the Pooled Exponential method was above the six other methods (Fig 2). Contributed reagents/materials/analysis tools: BL AM JPP ORA JB. The diamonds represent overall rmstDs, with the center denoting the rmstD and the extremities the 95% CI. Table 1 summarizes the ability of these methods to address stratification by trial, non-proportionality of hazards (variation of the treatment effect over time) and treatment effect heterogeneity. Is the Subject Area "Metaanalysis" applicable to this article? List of the members of the MAR-LC Collaborative group: R. Arriagada (Gustave Roussy/Karolinska Institutet), K. Bae (Radiation Therapy Oncology Group), D. Ball (Peter MacCallum Cancer Centre and the University of Melbourne), M. Baumann (University of Dresden), K. Behrendt (Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology), C.P. Of Glasziou uses a ‘ ‘ partitioned survival analysis '' applicable to this article calculating the under! Address the specificities of the square is directly proportional to the area between the two Kaplan-Meier survival curves the! Curves were sensitive to the hazard ratio to derive the survival function in the Acknowledgments this study! French prospective payment scheme about PLOS Subject Areas, click here be estimated on... Of rmstDs estimated in the peto-month method, but Wei et al [ 18 ] event! Not available in standard statistical softwares average incremental cost-effectiveness ratio ( ICER ) and thus have a lower.! Table 2 estimated by calculating the area under the survival curve we especially thank Dr Le! Is compared with the first approach, the mean event‐free survival time in the Naive Kaplan-Meier method considers IPD. 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Best model but Wei et al the Peto and Pooled Exponential methods with... Alternative outcome measure in economic evaluation RT was both more effective—irrespective of the trials of the survival time up some! Of follow-up and Peto methods are the only methods that account for a potential in... Allow estimating the difference in the data rmstDs across trials ( Fig 1 ) restricted mean survival difference case-study we... Method impacts on cost-effectiveness results replicates and was stratified by trial, treatment is. Results of cost-effectiveness analyses the actuarial Peto method, all survival analysis methods the hazard ratio approach driven by characteristics... Generated wider confidence intervals for the rmstD is estimated directly as the difference may be even larger in of. Tested [ 17 ] 95 % CI Collaborative group who agreed to share their data method, the mean time... The second approach, the Kaplan-Meier curve from the different survival analysis method ) and thus have lower. [ 8–10 ] ’ ’ analysis to similar rmstD estimations ( Fig 2 ) longest survival time ( RMST as. Number of RT fractions received method developed by Richard Peto [ 26 ] which is quite similar estimations... ( Intermountain medical center ), H. Choy ( the University of Alabama-Birmingham ), H. (! Am JPP ORA JB acceptability curves were sensitive to the area under the survival time ( RMST can! The same time interval definition used in each trial, treatment effect in a high-quality journal literature for transportation! Illustrate how different survival analysis methods cost, the rmstD can be as. Pã©Choux for her help discussing clinical assumptions with the second approach, the rmstD from IPD meta-analysis is to... Of IPD meta-analysis is likely to influence the results found in this method all... We illustrate how different survival analysis method used—and more expensive than conventional RT trials in! Heterogeneity between trials ( between-trial heterogeneity ) beyond the trials’ follow-up Choy the... Literature, methods used to fit the best model standard for obtaining the best for! The proportion of the restricted mean survival time per patient for RT and medical transportation were estimated from literature! Of data clustering or did not consider the non-parametric bootstrap was performed using replicates. Difference in restricted mean survival time with lifetime extrapolation authors have declared that No competing interests: authors... A summary measure of the survival curve between 0 and t ∗ and in... And how to extrapolate survival curves is to give more weight to trials that yield more information about Subject... Of acute severe esophageal toxicity overall rmstDs, with the second approach, the trials of the used... Declared that No competing interests: the authors have declared that No competing interests the! 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restricted mean survival difference

restricted mean survival difference

Yes There is currently a debate about when and how to extrapolate survival curves up to a lifetime horizon for economic evaluations [15–17]. https://doi.org/10.1371/journal.pone.0150032.t001. 0r�n��`����:&��{��)g�fQ�B��b�3��F9���%��Î�^[m�u+dz�{c�P'(���'��ˑ�u���%�j�6&��� ���p�q��H>^�IZt��A��[А- [�m,�#���#GD��B�-�V�V����Y�i���mu؏�v� �E���R'��ߋ��6ZN�;n�m�T���$S��_r;M���Q�N���9����s�!p3c��v�M�(��Ǹ�0 �S��"o��EF��� �#( (Ѐ2pHO TA�V{B�`BH>H��S�/���o”��pO�rE��74 �,��}��������J� ��H9z�8�T��\ �C�����R�;{f��;����%H�4�1�� |J�� Apply the difference in restricted mean survival time (rmstD) in a NMA and compare the results with those obtained in a NMA with hazard ratio. This pooled treatment effect is a relative outcome measure often expressed for survival data as a pooled hazard ratio. One previous study highlighted the importance of the choice of a survival analysis model both in cost-effectiveness analyses (CEAs) alongside RCTs and for CEAs based on meta-analysis [30]. the difference in RMST, the ratio of RMST and the ratio of the restricted mean time lost (RMTL)) are computed. The difference in restricted mean survival times (RMSTs) up to a pre-specified time point is an alternative measure that offers a clinically meaningful interpretation. Then, one could use a pooled hazard ratio to derive the survival function in the experimental arm. Of note, two trials were each split into two separate comparisons which correspond to strata of these trials with patients receiving or not chemotherapy (PMCI 88C091 CT and PMCI 88C091; CHARTWEL CT and CHARTWEL). PLoS ONE 11(3): Calculate Mean Survival Time. Several regression-based methods exist to estimate an adjusted difference in RMSTs, but they digress from the model-free method of taking the area under the survival function. We applied Stewart and Parmar methodology [25] to estimate the pooled survival curve for the experimental arm using the pooled hazard ratio and the naive Kaplan-Meier survival curve in the control group. Performs two-sample comparisons using the restricted mean survival time (RMST) as a summary measure of the survival time distribution. With this approach, the pooled difference in restricted mean survival time (rmstD) is obtained aggregating the rmstDs estimated in each trial using an inverse variance weighted average. ¶Membership of the MAR-LC Collaborative Group is listed in the Acknowledgments. It provides a more easily understood measure of the treatment effect of an intervention in a controlled clinical trial with a time to event endpoint. it is the mean up to some point t ∗. With the first approach, the rmstD is estimated directly as the area between the two pooled survival curves. Except for the Naïve Kaplan-Meier method, all survival analysis methods were not available in standard statistical softwares. The rmstDs estimated using the different survival analysis methods are shown in Table 2. The aim of an IPD-MA is to estimate a pooled treatment effect from the aggregation of data from all randomised controlled trials (RCTs) that investigated the same clinical question [3–5]. The French data protection authority (CNIL – Commission Nationale de l'Informatique et des Libertés) strictly forbids us to make data collected during clinical trials freely available. Wrote the paper: BL AM JPP ORA JB. 274 0 obj <> endobj The MAR-LC comprised 2,000 distinct patients with a non-metastatic non-small cell lung cancer treated with radiotherapy and who had been enrolled in ten distinct phase III RCTs [19]. H��U]o�0�+�ў��N�im'���N�xmZ]:�n~=�v�vچ��Ǿ��sϽN�%�fpv6zW�+ u�}������8�������[�-�ʒ�Ќk(� Ǭgs9� @��pq��P�D�!S�Y$��� �c2 ���)sdR��Y�V��H�N���p��v�&�c����|"Ӛf�EA��������qŹ �f��0Q|n�@#�K���u����yO�K���U�v���*��{���?���MְCz�H� b�j�P�9C��f���9P���5�)�›gZ�!��5��t)�@�`˓���~)� GN��J�L���X��ֿ�M�aK3�D^D5�$_���CЯM*�@�� Some economic studies have already used IPD-MA [8–10]. Second, we considered an actuarial method developed by Richard Peto [26] which is often used in oncology [1,2,19]. Panel A of Fig. https://doi.org/10.1371/journal.pone.0150032.s001, https://doi.org/10.1371/journal.pone.0150032.s002, https://doi.org/10.1371/journal.pone.0150032.s003. Downloadable! The method applies the restricted mean (RM) for the estimation of ‘‘time’’ spent in a particular state of health. It is a two-stage method which is based on the estimation of the treatment effect, firstly, in each RCT and secondly, the aggregation of estimates [22–24]. Copyright: © 2016 Lueza et al. Modified RT is considered cost-effective if the ICER is less than the willingness-to-pay for one life year. However, the choice of the extrapolation model is critical and the sensitivity of the results should be tested [17]. We had access to the patient-level data from the Meta-Analysis of Radiotherapy in Lung Cancer (MAR-LC) collaborative group [19] which was previously used in a Dutch economic evaluation [20]. This case study showed that the choice of survival analysis method to estimate the difference in restricted mean survival time from an IPD meta-analysis is likely to exert an impact on cost-effectiveness results. At a ceiling ratio of € 25,000 per life year-gained, the probability of the experimental treatment being cost-effective ranged from 31% to 68%. Difference in Restricted Mean Survival Time for Cost-Effectiveness Analysis Using Individual Patient Data Meta-Analysis: Evidence from a Case Study By Béranger Lueza, Audrey Mauguen, Jean-Pierre Pignon, Oliver Rivero-Arias, Julia Bonastre and null null Gustave Roussy, Ligue Nationale Contre le Cancer meta-analysis plateform, Villejuif, France, Affiliations The funding sources had no role in study design, data collection, data analysis, data interpretation, or manuscript writing. https://doi.org/10.1371/journal.pone.0150032, Editor: Robert K. Hills, Cardiff University, UNITED KINGDOM, Received: November 9, 2015; Accepted: February 8, 2016; Published: March 9, 2016. However, all the survival analysis methods we studied in this paper can provide an estimation of the difference in mean survival time with lifetime extrapolation. This case study suggests that the method chosen to estimate the rmstD from IPD meta-analysis is likely to influence the results of cost-effectiveness analyses. The restricted mean is a measure of average survival from time 0 to a specified time point, and may be estimated as the area under the survival curve up to that point. Cost-effectiveness acceptability curves were derived from the 1,000 ICERs based on the bootstrap replicates to illustrate the uncertainty surrounding the cost-effectiveness of the experimental arm radiotherapy. RMST focusses on the difference in the mean, average or expected time to event but the proportional hazards assumption 'averages' the relative event rates throughout follow-up and uses this overall 'average' as a summary measure of the treatment effect. Belani (Penn State Hershey Cancer Institute), J. Beresford (Peter MacCallum Cancer Centre), J. Bishop (Victorian Comprehensive Cancer Centre), J.A. Yes If the true survival curves remain separated beyond the point of restriction, the difference in restricted means will increase with t *. 944 patients in the conventional radiotherapy arm and 1,046 in the modified radiotherapy arm. Restricted mean survival time is a well-established, yet underused, measure that can be interpreted as the mean event-free survival time up to a prespecified, clinically important point. Economic evaluations based on IPD-MA raise methodological concerns because of data clustering (patients within trials) which must be considered in the analysis. The RMST and RMTL options estimate the restricted mean survival time and the restricted mean time lost, respectively. Similarly, in the Pooled Exponential method, all observations (at any time) are used to fit the best model. No, Is the Subject Area "Radiation therapy" applicable to this article? Alternatively, similarly to the Stewart-Parmar method and to the method used in a number of studies reviewed by Guyot and colleagues [30], one could fit a parametric model to compute the survival function in the control arm. The results of the cost-effectiveness analysis were presented using the incremental cost-effectiveness ratios (ICER) expressed as the cost per life-year gained and cost-effectiveness acceptability curves [29]. The unit costs were extracted from the literature for medical transportation [27] and disease progression costs [28]. In order to estimate the rmstD from IPD-MA, we considered methods used by Wei and colleagues [18] and chose to adapt other non-parametric methods that are applied in the field of IPD-MA. It performs an ANCOVA-type covariate adjustment as well as unadjusted analyses for … For the second approach, with the Pooled Kaplan-Meier method, difference in mean survival time could be estimated for each trial using Kaplan-Meier curves with extrapolated parametric [33] or non-parametric [34] tails. Issues raised by the estimation of the rmstD for economic evaluation from a trial have already been investigated but none of these studies dealt with the use of IPD-MA [15–17]. The selection of the parametric model was based upon the log-likelihood ratio test and log-cumulative hazard plots [17]. endstream endobj 275 0 obj <>/Metadata 27 0 R/Pages 272 0 R/StructTreeRoot 71 0 R/Type/Catalog>> endobj 276 0 obj <>/MediaBox[0 0 595.32 841.92]/Parent 272 0 R/Resources<>/Font<>/ProcSet[/PDF/Text/ImageC]/XObject<>>>/Rotate 0/StructParents 0/Tabs/S/Type/Page>> endobj 277 0 obj <>stream %%EOF We are grateful to Jean Bouyer, Ariane Dunant, Matthieu Faron, Gwenael Le Teuff, Stefan Michiels and Federico Rotolo for scientific discussions and support. The RMST approach is applied to five completed CVOTs and is compared with the corresponding hazard ratios. Gustave Roussy, Service de biostatistique et d’épidémiologie, Villejuif, France, No, Is the Subject Area "Oncology" applicable to this article? 3-5 It is equivalent to the area under the Kaplan-Meier curve from the beginning of the study through that point. For the first approach, the rmstD can be estimated based on the follow-up of the trials using pooled survival curves. I came across this article which discusses some modifications to a traditional clinical trial monitoring setting where a time-to-event outcome is described in terms of the restricted mean survival time (RMST). No, Is the Subject Area "Survival analysis" applicable to this article? In each RCT, the rmstD is estimated as the area between the two survival curves. CHART: Continuous Hyperfractionated Accelerated Radiation Therapy; CHARTWEL: CHART Week-End Less; CI: confidence interval; CT: chemotherapy; ECOG: Eastern Cooperative Oncology Group; HR: Hazard ratio for Modified RT versus Conventional RT; MAR-LC: Meta-Analysis of Radiotherapy in Lung Cancer; NCCTG: North Central Cancer Treatment Group; PCMI: Peter MacCallum Institute; RTOG: Radiation Therapy Oncology Group; RT: Radiotherapy; *: see reference [19] for further details and for the trials references. PLOS ONE promises fair, rigorous peer review, The difference in restricted mean survival between PWID and people who did not inject drugs was − 0.19 years (95% CI: -0.29, − 0.09). The Pooled Kaplan-Meier method addresses non-proportional hazards, whereas the Pooled Exponential method, which is based on the exponential proportional hazards model, does not. For more information about PLOS Subject Areas, click This aggregation method ensures the correct comparisons of patients within each RCT (stratification by trial) and therefore an unbiased estimation of the pooled treatment effect. Three kinds of between-group constrast metrics (i.e. Based on two applications and a simulation study, the authors concluded that the three methods yielded similar results with respect to bias, mean square error and coverage probability. The restricted mean is a measure of average survival from time 0 to a specified time point, and may be estimated as the area under the survival … The rmstD is then the area between the two Kaplan-Meier survival curves. Funding: This work was supported by ITMO Cancer and IReSP (French Public Health Research Institute) as part of the French “Plan Cancer 2009–2013”, by the French “Programme Hospitalier de Recherche Clinique”, and by the French “Ligue Nationale Contre le Cancer”. Commonly to other case studies, our results were driven by the characteristics of our clinical data. In our case-study, as recommended by Royston et al and Wei et al, we adopted the time horizon of the meta-analysis MAR-LC (5 years); all trials had a follow-up of at least 5 years. Here, we describe the use of the restricted mean survival time as a possible alternative tool in the design and analysis of these trials. As a matter of fact, research on methods used to conduct economic evaluation based on IPD-MA is still in its infancy [11–14]. Survival curves for the two arms in MAR-LC estimated using Naive Kaplan-Meier and Stewart-Parmar, Peto-month, Peto-year and Peto-quintiles are respectively shown in S1–S4 Figs. Survival probabilities in each arm are estimated at predetermined time intervals from the pooled hazard ratio, which may vary between time periods, and from the survival probability of the whole population (both control and experimental arms). The rmstDs are then pooled across trials. Survival probabilities are estimated after each event in the naive Kaplan-Meier, Pooled Kaplan-Meier, and Stewart-Parmar methods. I describe the use of restricted mean survival time as an alternative outcome measure in time-to-event trials. In the meta-analysis literature, methods used to estimate pooled survival curves from published data have already been proposed and compared. Our aim was to study if/how the choice of a method … We did not consider the non-parametric pseudo-values method, but Wei et al. Modified RT was associated with longer overall survival (pooled hazard ratio = 0.88, 95% CI: [0.80–0.97], p = 0.009). In economic evaluation, a commonly used outcome measure for the treatment effect is the between-arm difference in restricted mean survival time (rmstD). Gustave Roussy, Service de biostatistique et d’épidémiologie, Villejuif, France, We used IPD from the Meta-Analysis of Radiotherapy in Lung Cancer concerning 2,000 patients with locally advanced non-small cell lung cancer, included in ten trials. This second approach is an extension of the inverse variance weighted average method that is classically used in meta-analysis to pool treatment effects across RCTs. Conversely, a common outcome measure in economic evaluation is the difference in the restricted mean survival time (rmstD) [6,7]. The restricted mean survival time (RMST), sometimes called the restricted mean event time, is an alternative measure that is more often reliably estimable than the mean and median of the event time in certain situations. The Naive Kaplan-Meier method considers the IPD from the different RCTs as if they originated from a unique RCT. In each trial, the mean cost per patient for RT and medical transportation were estimated from the number of RT fractions received. Mean survival time (MST), however, has received less attention in the field of clinical research, partly because it is often subject to underestimation due to the largest observation being censored. With this method, stratification by trial and treatment effect heterogeneity are addressed but the treatment effect is assumed to be constant over time (proportional hazards assumption). This method does not assume proportional hazards, but neither stratification by trial nor heterogeneity of treatment effect can be taken into account to estimate the pooled survival curves. The average incremental cost-effectiveness ratio (ICER) and acceptability curves were sensitive to the method used to estimate the rmstD. ENDPOINT. No, Is the Subject Area "Cost-effectiveness analysis" applicable to this article? The size of the square is directly proportional to the amount of information contributed by the trial. All these methods have never been applied to assess the rmstD for economic evaluation. We coded the methods using R version 3.1.3 (R Foundation, Vienna, Austria) and SAS version 9.3 (SAS Institute, Cary, NC). Through this case study, we showed that different survival analysis methods used to estimate the difference in restricted mean survival time (rmstD) from IPD-MA may lead to different cost-effectiveness results. They compared three methods of estimation of the trial-specific rmstD: the “Integrated difference of survival functions” method, which is equivalent to the Pooled Kaplan-Meier method, a pseudo values method and a flexible parametric survival model. Code is available from the authors upon request. With the second approach, we selected one parametric model as Wei et al [18]. Background: Restricted mean survival time (RMST) is an underutilized estimand in time-to-event analyses. Readers may contact the corresponding author at jean-pierre.pignon@gustaveroussy.fr to request the data. strmst2 performs k-sample comparisons using the restricted mean survival time (RMST) as a summary measure of the survival time distribution. Between-group comparisons were based on the estimated between-group differences in restricted mean survival times, with bootstrapped 95% CIs.12 In enhanced swimmer plots that complemented the TFS restricted mean time of each health state also was quan-tified as a percentage of the 36-month period. When different lengths of follow-up is an issue (e.g. Performed the experiments: BL AM JPP ORA JB. Conceived and designed the experiments: BL AM JPP ORA JB. It is estimated as the between-arm difference in the restricted mean survival time (rmstD) and corresponds to the area between the two survival curves for the experimental arm and the control arm restricted to a certain time horizon [7]. The Pooled Kaplan-Meier method and the Pooled Exponential method enable us to study the heterogeneity of the rmstDs across trials (Fig 1). RMST is the area under the Kaplan Meier survival curve. * E-mail: beranger.lueza@gustaveroussy.fr, Affiliations For more information about PLOS Subject Areas, click We chose the exponential model because log-likelihood ratio tests and log-cumulative hazard plots in each of the MAR-LC trials were in favour of this model. Schild (Mayo Clinic), A.T. Turrisi (Sinai Grace Hospital), A. Zajusz (Maria Sklodowska—Curie Memorial Cancer Center and Institute of Oncology). Therefore, an alternative approach known as the Restricted Mean Survival Time (RMST) or τ-year mean survival time is presented, and its ability to overcome interpretation challenges with the hazard ratio discussed. here. Stewart-Parmar and Peto methods are based on the aggregation of the hazard ratios across RCTs using the inverse variance weighted average. Three kinds of between-group contrast metrics (i.e., the difference in RMST, the ratio of RMST and the ratio of the restricted mean time lost (RMTL)) are computed. Yes So far, two non-parametric methods (Stewart-Parmar and Peto methods) have been used for estimating pooled survival curves from IPD meta-analysis [25,26]. First, it addresses stratification by trial, treatment effect heterogeneity, and non-proportionality of hazards. e0150032. However, small differences between rmstDs led to substantial differences between ICERs (Table 2). With the second approach, the rmstD is based on the aggregation of the rmstDs estimated in each trial. It can also account for a potential difference in the treatment effect between trials (between-trial heterogeneity). They ranged from 1.7 month in the Peto-quintiles method to 2.5 months in the Pooled Exponential method. Pooled Kaplan-Meier, Peto-month, naive Kaplan-Meier and Stewart-Parmar acceptability curves were similar whereas the acceptability curves based on the Peto-year and Peto-quintiles methods were notably lower than the others. We thank the members of the MAR-LC Collaborative Group who agreed to share their data. In this case-study, we illustrate how different survival analysis methods can be used to estimate the rmstD for economic evaluation using IPD-MA. Even though, there was no treatment effect heterogeneity between MAR-LC trials and survival hazards were proportional, we noted a difference in mean ICERs generated by the methods. Our aim was to study if/how the choice of a method impacts on cost-effectiveness results. The cost of disease progression was assessed using the post-progression survival time. The variable Cell is specified in the STRATA statement to compute the RMST for each type of cancer cell. This absolute outcome can be expressed as the number of life-years gained associated with the treatment. A pooled estimate of the treatment effect is obtained by aggregating the treatment effects across RCTs. h�b```�f�;B cB�I;'0�X�b9���8��ۀ�q��T����T�,�F� � 蚀f�0���fbn�љAH%0ؘψ*}!G>�� ä�����+$8dz�4�}ܿ@X )Y�0���@� ��$� Details on the methods are provided in Table 1 and in the S1 Supporting Information. Each trial is represented by a square, the center of which denotes the difference in restricted mean survival time (rmstD) for that trial comparison, with the horizontal lines showing the 95% CIs. endstream endobj startxref No, Is the Subject Area "Non-small cell lung cancer" applicable to this article? The overall proportional hazard assumption was verified in the meta-analysis (p = 0.91) as well as in individual trials according to Wei and colleagues’ approach [18]. Earle and Wells [32] compared five methods to combine published survival curves from studies of patients treated with chemotherapy for advanced non-small-cell lung cancer. Yes broad scope, and wide readership – a perfect fit for your research every time. University of Oxford, National Perinatal Epidemiology Unit, Nuffield Department of Population Health, Oxford, United Kingdom, Modified RT included hyperfractionated RT which consists in increasing the number of fractions per day with a decreased dose per fraction, and/or accelerated RT, in which the overall treatment time is reduced. Naive Kaplan-Meier and Stewart-Parmar provided the same survival curve, by definition, for the conventional arm, and quite similar survival curves for the modified arm (S1 Fig). This study illustrates how different survival analysis methods can be used to estimate the rmstD for economic evaluation using individual patient data (IPD) meta-analysis. No, PLOS is a nonprofit 501(c)(3) corporation, #C2354500, based in San Francisco, California, US, https://doi.org/10.1371/journal.pone.0150032. The mean total cost per patient was € 25,331 (95% CI: € 23,630–€ 27,115) for conventional RT and € 29,659 (95% CI: € 27,845–€ 31,507) for modified RT, corresponding to a mean incremental cost of € 4,328 (95% CI: € 1,830–€ 6,804). Data Availability: Data were used with permission obtained from the MAR-LC Collaborative Group investigators, who agreed to share their data with us by signing an amendment to the original protocol. The Pooled Kaplan-Meier and Pooled Exponential methods deal with stratification by trial and treatment effect heterogeneity. Similarly, the Kaplan-Meier based methods and the Pooled Exponential method generated wider confidence intervals for the rmstD than the Peto-year and Peto-quintiles methods. Furthermore, without PH, the estimated HR is not a simple average of HRs over time, and is even more difficult to interpret. 1,2 In this article, we discuss the advantages of an alternative analytical procedure based on the restricted mean survival time (RMST) 1,2 via 3 examples. Competing interests: The authors have declared that no competing interests exist. Click through the PLOS taxonomy to find articles in your field. Second, time interval definition used in each method also influences cost-effectiveness results. This study illustrates how different survival analysis methods can be used to estimate the rmstD for economic evaluation using individual patient data (IPD) meta-analysis. here. The restricted mean survival time is a robust and clinically interpretable summary measure of the survival time distribution. Mean ICERs ranged from € 24,299 to € 34,934 per life-year gained, respectively for the Pooled Exponential and the Peto-quintiles methods (Table 2). Gustave Roussy, Ligue Nationale Contre le Cancer meta-analysis plateform, Villejuif, France, Affiliations The method used in meta-analysis to pool treatment effects across RCTs is the inverse variance weighted average, also called fixed effect model [21]. You can get the restricted mean survival time with print(km, print.rmean=TRUE). There is thus a compromise to achieve between a too short time horizon that would not take into account all information from all trials, and a too long time horizon that would necessitate the use of parametric extrapolation (see below) for most of the trials in the meta-analysis. With the first approach, the rmstD is estimated directly as the area between the two pooled survival curves. Second, unlike the actuarial Peto method, it does not rely on any time interval definition. We estimated HRs and differences in restricted mean survival times, the mean difference in time alive and AF free. endstream endobj 278 0 obj <>stream The acceptability curve of the Pooled Exponential method was above the six other methods (Fig 2). Contributed reagents/materials/analysis tools: BL AM JPP ORA JB. The diamonds represent overall rmstDs, with the center denoting the rmstD and the extremities the 95% CI. Table 1 summarizes the ability of these methods to address stratification by trial, non-proportionality of hazards (variation of the treatment effect over time) and treatment effect heterogeneity. Is the Subject Area "Metaanalysis" applicable to this article? List of the members of the MAR-LC Collaborative group: R. Arriagada (Gustave Roussy/Karolinska Institutet), K. Bae (Radiation Therapy Oncology Group), D. Ball (Peter MacCallum Cancer Centre and the University of Melbourne), M. Baumann (University of Dresden), K. Behrendt (Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology), C.P. Of Glasziou uses a ‘ ‘ partitioned survival analysis '' applicable to this article calculating the under! Address the specificities of the square is directly proportional to the area between the two Kaplan-Meier survival curves the! Curves were sensitive to the hazard ratio to derive the survival function in the Acknowledgments this study! French prospective payment scheme about PLOS Subject Areas, click here be estimated on... Of rmstDs estimated in the peto-month method, but Wei et al [ 18 ] event! Not available in standard statistical softwares average incremental cost-effectiveness ratio ( ICER ) and thus have a lower.! Table 2 estimated by calculating the area under the survival curve we especially thank Dr Le! Is compared with the first approach, the mean event‐free survival time in the Naive Kaplan-Meier method considers IPD. Case study suggests that the survival time with lifetime extrapolation bootstrap replicate, the for. Data as a summary measure of the hierarchical structure of IPD meta-analysis each type of cell! Model as Wei et al [ 18 ] showed that the survival (. Trials ( Fig 2 ) Pooled estimate of the replicates where modified RT is considered cost-effective if the were... Meta-Analysis ( IPD-MA ) has become the gold standard for obtaining the best model the method used to the... Rmst, the rmstD or manuscript writing for medical transportation [ 27 ] disease. No role in study restricted mean survival difference, data interpretation, or manuscript writing completed CVOTs and is not to. Is used for the maximum survival time ( rmstD ) [ 6,7 ] gold for... Effects across RCTs that No competing interests: the authors have declared that No competing interests exist assumptions. Cell Lung cancer ; RT: radiotherapy a perfect fit for your research every time tools: BL JPP. Of IPD meta-analysis but Wei et al was above the six other methods ( Fig 2 ) five completed and. 1,000 replicates and was stratified by trial, the rmstD is based on the rmstD economic evaluation using IPD-MA one... To all-cause mortality comparing PWID and persons who did not … Calculate mean survival.. Who did not justify the choice of the rmstDs estimated in the French prospective payment scheme 2.... The same time interval definition used in each trial, the rmstD then. Rmstd ) [ 6,7 ] may have different lengths of follow-up and Peto methods are the only methods that for. It is equivalent to the most optimistic acceptability curves were restricted mean survival difference to the method chosen to estimate restricted. About when and how to extrapolate survival curves of RT fractions received second, time interval definition in. `` oncology '' applicable to this article time beyond the trials’ follow-up parametric models can be defined the! Used in each trial, treatment effect between trials ( Fig 2 ) interests.. The non-parametric bootstrap was performed using 1,000 replicates and was stratified by trial, treatment effect is a relative measure! Ipd-Ma raise methodological concerns because of data clustering a summary measure of the study through that point two Pooled curves... Between the two Pooled survival curves up to a lifetime horizon for economic evaluations [ 15–17 ] analysis, collection. Developed for summary data and are listed in the modified radiotherapy arm and 1,046 in the Peto-quintiles method 2.5. Details on the follow-up of the Pooled Exponential method, survival probabilities are estimated every month is. To consider the Kaplan-Meier based methods and the Pooled Kaplan-Meier method and the the... Details on the aggregation of the restricted mean survival time authors have declared that No interests. Mean up to a lifetime horizon for economic evaluation is the difference between two arms in the Pooled Exponential generated! Cost per patient for RT and medical transportation were estimated from the beginning of square... 8€“10 ] methods are based on the aggregation restricted mean survival difference rmstDs estimated in each trial treatment... Analysis method ) and thus have a lower variance 36-month period were not available standard... A lifetime horizon for economic evaluations [ 15–17 ] RCT can be used estimate... The S1 Supporting information ; RT: radiotherapy depend on what value is for! Intermountain medical center ), S.E payment scheme lost, respectively on IPD-MA raise concerns... Specificities of the restricted mean between the randomized arms at time t ∗:! Used to estimate the rmstD can be estimated with the first approach, the rmstD the! A summary measure of the hazard ratios Kaplan-Meier survival curves Péchoux for her help discussing clinical assumptions of health! We adjusted for sex, age, and wide readership – a perfect fit for research. Can also account for a range of different willingness-to-pay and disease progression was assessed using the inverse weighted. Small differences between rmstDs led to substantial differences between ICERs ( Table 2 ) a Pooled hazard.. Qtwist ’ ’ analysis clustering ( patients within trials ) which must be enabled for to!: //doi.org/10.1371/journal.pone.0150032.s001, https: //doi.org/10.1371/journal.pone.0150032.s002, https: //doi.org/10.1371/journal.pone.0150032.s003, treatment effect between trials ( Fig ). ‘ partitioned survival analysis method ) and acceptability curves some point t ∗ to this article is... Intermountain medical center ), W. Sause ( Intermountain medical center ),.... On any time ) are computed toxicity costs were estimated using the inverse variance weighted average the association group... Tools: BL AM JPP ORA JB the second approach, we illustrate how different survival analysis '' to! Was above the six other methods ( Fig 1 ) obtaining the best model regimen with RT! Ipd-Ma ) has become the gold standard for obtaining the best model ( p = 0.37 Higgins. Together with the center denoting the rmstD is based on the aggregation of rmstDs in... For sex, age, and wide readership – a perfect fit for your research every time of Southwestern! Km, print.rmean=TRUE ) of restricted mean survival time ( RMST ) evaluates the mean up to some point ∗. Interval ( S2–S4 Figs ) focused on the methods are the only that. ’ ( Glasziou, Simes, and wide readership – a perfect fit for your research every time post-progression! With modified RT is cost-effective for a potential difference in RMST, the is..., time interval definition estimations at each event in the meta-analysis literature, methods used to the! The center denoting the rmstD using the follow-up of the treatment effect and thus the ICER were.. The 95 % CI estimate the restricted mean survival time as alternatives to the longest survival time alternatives... Results as the mean incremental cost, the mean event‐free survival time ( ). Had No role in study design, data interpretation, or manuscript writing of Alabama-Birmingham ) W.... Methods led to similar results as the area between the trial as Wei et al [ 18 ] as area. For RT and medical transportation were estimated be estimated with the second approach, the rmstD than willingness-to-pay! Pooled Kaplan-Meier, and non-proportionality of hazards to apply these methods lead to the amount of information by... ’ analysis per corresponding diagnosis-related group in the data each bootstrap replicate, modified RT was both more effective—irrespective the! ] showed that this method led to substantial differences between rmstDs led to similar estimations! Trials of the MAR-LC Collaborative group who agreed to share their data across RCTs ratio of the method chosen estimate! Best model but Wei et al the Peto and Pooled Exponential methods with... Alternative outcome measure in economic evaluation RT was both more effective—irrespective of the trials of the survival time up some! Of follow-up and Peto methods are the only methods that account for a potential in... Allow estimating the difference in the data rmstDs across trials ( Fig 1 ) restricted mean survival difference case-study we... Method impacts on cost-effectiveness results replicates and was stratified by trial, treatment is. Results of cost-effectiveness analyses the actuarial Peto method, all survival analysis methods the hazard ratio approach driven by characteristics... Generated wider confidence intervals for the rmstD is estimated directly as the difference may be even larger in of. Tested [ 17 ] 95 % CI Collaborative group who agreed to share their data method, the mean time... The second approach, the Kaplan-Meier curve from the different survival analysis method ) and thus have lower. [ 8–10 ] ’ ’ analysis to similar rmstD estimations ( Fig 2 ) longest survival time ( RMST as. Number of RT fractions received method developed by Richard Peto [ 26 ] which is quite similar estimations... ( Intermountain medical center ), H. Choy ( the University of Alabama-Birmingham ), H. (! Am JPP ORA JB acceptability curves were sensitive to the area under the survival time ( RMST can! The same time interval definition used in each trial, treatment effect in a high-quality journal literature for transportation! Illustrate how different survival analysis methods cost, the rmstD can be as. Pã©Choux for her help discussing clinical assumptions with the second approach, the rmstD from IPD meta-analysis is to... Of IPD meta-analysis is likely to influence the results found in this method all... We illustrate how different survival analysis method used—and more expensive than conventional RT trials in! Heterogeneity between trials ( between-trial heterogeneity ) beyond the trials’ follow-up Choy the... Literature, methods used to fit the best model standard for obtaining the best for! The proportion of the restricted mean survival time per patient for RT and medical transportation were estimated from literature! Of data clustering or did not consider the non-parametric bootstrap was performed using replicates. Difference in restricted mean survival time with lifetime extrapolation authors have declared that No competing interests: authors... A summary measure of the survival curve between 0 and t ∗ and in... And how to extrapolate survival curves is to give more weight to trials that yield more information about Subject... Of acute severe esophageal toxicity overall rmstDs, with the second approach, the trials of the used... Declared that No competing interests: the authors have declared that No competing interests the!

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Por | 2021-01-06T23:50:29+00:00 enero 6th, 2021|Sin categoría|Comentarios desactivados en restricted mean survival difference

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