This manuscript reports on the novel research strategies currently being investigated to improve outcomes for patients with poor prognosis cancers. m 10.1016/0304-4076(94)01612-4. s , so that. Multilevel modelling has rapidly become established as the appropriate tool for modelling data with complex hierarchical structures. k ŝ the estimated KM survival probability at the previous co-ordinate where we estimate that an event occurred, last(k). - ) ≠nris Dynamic and insightful pre-clinical research programs are a critical component in addressing this need, but challenges exist. Health care systems around the world are under pressure to reform and to improve the quality of service delivery. , weighted by the remaining time relative to the time already elapsed, rounded to the nearest integer. 10.1002/1097-0142(19900301)65:5<1155::AID-CNCR2820650521>3.0.CO;2-7. 2006, 354: 567-78. k Earle C, Wells G: An Assessment of Methods to Combine Published Survival Curves. u We encourage users to undertake the initial digitization and pre-processing with scrupulous care. Published survival curves are almost always based on the KM method justifying our approach of using inverted KM equations instead of life-table equations and solving at the same time the problem of pre-specification of intervals. We then show how the algorithm can be adapted when the number at risk is only reported at the beginning of the study ('no numbers at risk' case), when the total number of events is not reported ('no total events' case), and when neither of these are reported ('neither' case). For each i, lower 2008, 27: 4381-4396. The illustrative example uses KM curves, reproduced in Figure 1, on locoregional control events in head and neck cancer [12]. Kaplan Meier curves and Cox HRs based on reconstructed data were estimated using the R routines survfit and coxph. i Article  The KM curves, extracted from a .pdf article, are read into the software, the axes are defined, and then the analyst uses mouse-clicks to select points to read off from the curve. t The validation exercise established that reproducibility and accuracy of reconstructed statistics was excellent, especially for median survival and probability of survival. These authors contributed equally to this work. n However, as we have seen in the results section, if the total number of events and the numbers at risk other than at time zero are not provided, the algorithm may produce poor results. We use digital software to read in the coordinates of the KM curves from the published graph and we use the information on numbers at risk, often published at four or five time points under the x-axis of the KM graph, and total number of events, where available, to reconstruct the Kaplan-Meier data for each arm. d The resulting T r 2003, 14 (3): 341-354. This topic is called reliability theory or reliability analysis in engineering, duration analysis or duration modelling in economics, and event history analysis in sociology. 2008, Lippincott Williams & Wilkins, Third. Royston P, Parmar MKB: Flexible parametric proportional-hazards and proportional-odds models for censored survival data, with application to prognostic modeling and estimation of treatment effects. We distribute the c=1,…,nce i low survival cancer; immuno-oncology; insulin signaling; chromatin re-modelling; transforming growth factor-beta signaling, Help us to further improve by taking part in this short 5 minute survey, Association of Genetic Polymorphisms and Serum Levels of IL-6 and IL-8 with the Prognosis in Children with Neuroblastoma, Radiosensitizing Pancreatic Cancer with PARP Inhibitor and Gemcitabine: An In Vivo and a Whole-Transcriptome Analysis after Proton or Photon Irradiation, transforming growth factor-beta signaling. t We then describe the inputs required for the algorithm, before presenting the algorithm itself. n 2003, Boca Raton: Chapman & Hall/CRC, Second. i For the evidence syntheses, i.e. 1 To assess the differences between the reconstructed statistics and the original ones, the natural scale was used for the survival probabilities, while the log scale was used for medians, HRs and their uncertainties. Earle [10] evaluated the reproducibility of using digitized software to extract the data by reporting an intraclass correlation coefficient. Finally, Ouwens [8] and Jansen [9] digitise the KM graphs at particular time points and use the number at risk at the beginning of the interval, if this is reported, or conservatively assume no censoring if it is not. u i Here, we discuss research progress aimed at gaining a better understanding of the molecular and cellular changes in tumor cells and the surrounding stroma, presented at the 56th Irish Association for Cancer Research (IACR) Annual Conference. Statistics in medicine. [ i c STEP 4. http://www.nicedsu.org.uk/Crossover%20and%20survival%20-%20final%20DSU%20report.pdf, http://www.biomedcentral.com/1471-2288/12/9/prepub, Additional file 1: The algorithm (R coding).pdf. Collett D. Modelling survival data in medical research. The data should be sufficient: every step seen in the figures should have been captured during the data extraction. “A New Dataset on Infant Mortality Rates, 1816-2002.” Journal of Peace Research 44 (2007):743. We fitted a standard two-way ANOVA with repeated measures to the differences between the reconstructed outcomes and the original outcomes, either on the natural or the log scale depending on the statistic considered. To improve patient outcomes, ultimately, the cancer research community must meet and overcome these challenges, leading to improved approaches to treat the most difficult cancers. - ^ ^ Data Manager. In the method section, we briefly describe the Kaplan-Meier estimation method. k for each source of variation. k+1= trisk We thank Laure Weijers and Cora Verduyn for reconstructing the statistics of six pairs of KM curves on two occasions using our method. By taking the exponentials of these values, we obtain that the mean error is on average a factor of exp (0.011), or 1.1% (95%CI: 0.4%; 1.8%). ^ Evaluation and the Health Professions. r for each extracted KM co-ordinate k = 1,..., N, we can derive the IPD that would generate that data. i The first column is the interval, the second column shows the time, the third column shows the row of the extracted co-ordinates that the time corresponds to, the fourth column is the upper row of the extracted co-ordinates for which the time is less than the following time at which we have a number at risk and the last column is the number at risk. d These published summary results and their corresponding reconstructed summary results are presented in Table 3. Kimball. Reproducibility variation is also exceptionally low at 0.006 on the log scale, corresponding to a 0.6% geometric standard deviation. By using this website, you agree to our All authors have been involved in drafting the manuscript. 10.1002/sim.1303. We then use the reported total number of events, totevents. Received: 22 December 2020 / Revised: 22 January 2021 / Accepted: 26 January 2021 / Published: 30 January 2021. k 1 n The validation results are summarised in Table 4. i The primary objective of this previous work was neither the reconstruction of Kaplan Meier data nor the reconstruction of life-table data, but was a necessary step that had to be taken in order for the authors to illustrate methods for combining survival data from several studies. Schoenfeld D. Partial residuals for the proportional hazards regression model. Multiple parameter distributions can be implemented [17–19], or flexible spline approaches [20]. Experience with past epidemics like the 2014 West Africa Ebola … ^ 2005, 97: 1262-1271. The life-table data is then reconstructed as a series of conditionally independent binomial distributions. = We first form an initial guess for the number censored on interval i. In contrast to survival probabilities and medians, both the MAE and the exemplar variance deteriorate markedly as less and less information is provided. t 2002, 21: 3337-3351. PubMed  We cannot identify the exact censoring pattern within each interval, and so we are forced to make an assumption. Google Scholar. BMJ. School of Social and Community Medicine, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol, BS8 2PS, UK, Mapi Consultancy, De Molen 84, 3995 AX, Houten, The Netherlands, You can also search for this author in https://doi.org/10.3390/cancers13030528, Subscribe to receive issue release notifications and newsletters from MDPI journals, You can make submissions to other journals. k The figure extracted from the .pdf should not be of low quality (for instance, blurry figure and/or poor numerical axis scale); otherwise the user may struggle to extract accurate data via the digitising software. . Using the algorithm, we obtain reconstructed IPD and it allows us to reconstruct the KM curves as shown in Figure 2. and upper STEP 1. Shore T, Nelson N, Weinerman B: A meta-analysis of stages I and II Hodgkin's disease. The data should also be consistent: the probability of experiencing the event decreases with time, and it should be verified that this is always the case for the data points extracted. The resulting mean bias, or mean error (ME) reflects systematic over- or underestimation. , ∞). , is equal to the reported total number of events, totevents or until the estimated total number of events is less than the reported total number of events but the total number of censoring in the last interval, nce 2, we obtain that p Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, Jones CU, Sur R, Raben D, Jassem J, Ove R, Kies MS, Baselga J, Youssoufian H, Amellal N, Rowinsky EK, Ang KK: Radiotherapy plus Cetuximab for Squamous-Cell Carcinoma of the Head and Neck. The components of variance were exemplar, observer, exemplar × observer interaction, and within-cell error. While the available evidence indicates the direct impact of COVID-19 on child and adolescent mortality to be very limited, the indirect effects stemming from strained health systems, household income loss, and disruptions to care-seeking and preventative interventions like vaccination may be substantial and widespread. nrîs and trisk The MAE error is of the same order. 2nd ed. Thus, we would expect that 68% of the observations are within 0.6% (95% CI: 0.4%; 1.2%) either side of the original median. In order to enhance the quality of secondary data analyses, we propose a method which derives from the published Kaplan Meier survival curves a close approximation to the original individual patient time-to-event data from which they were generated. Health Economics and Outcomes Research (HEOR) Ltd is an independent consultancy specialising in the application of health economic techniques to support pharmaceutical pricing, health technology assessment (HTA) and value assessment, reimbursement, and market access activities. These intervals are designed to be such that at least one event occurs at the start of each interval. The statements, opinions and data contained in the journals are solely Williamson PR, Marson AG, Tudur C, Hutton JL, Chadwick D: Individual patient data meta-analysis of randomized anti-epileptic drug monotherapy trials. Fiocco [6] assumes a Poisson distribution and uses log-linear modelling based on estimated data using the same approach as Parmar. k This severely limits the way in which RCTs with survival time data can be included in any kind of secondary data analyses, whether as part of a cost-effectiveness analyses (CEA) or in an analysis of treatment efficacy. This gives a further indication of the accuracy of the method. 2010, 340: c869-10.1136/bmj.c869. Pan J-N: Evaluating the Gauge repeatability and reproducibility for different industries. Research Synthesis Methods. k Reproducibility and accuracy of the method was evaluated for each of the 4 different levels of information ('all information', 'no numbers at risk', 'no total events' and 'neither'). CONSORT guidelines recommend that for each primary and secondary outcome "study results should be reported as a summary of the outcome in each group, together with the contrast between the groups, known as the effect size" [1]. To assess accuracy we examined the mean difference between the reconstructed statistics and the original ones. The PanCancer Atlas provides a detailed genomic analysis of molecular and clinical data from more than 10,000 tumors that gives cancer researchers an unprecedented understanding of how, where, and why tumors arise in humans. There is a strong case to be made that the same statistical model should be used for both efficacy and CEA analyses [13]. u First, aggregated results from time-to-event trials may be reported as medians or as HRs, but it is hard to combine trials reporting medians with trials reporting HRs without making distributional assumptions. Consort guidelines recommend instead, that for survival time, the measure of effect could be the hazard ratio or difference in median survival time. Stat Med. t This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. t The approach chosen is similar to what is referred to in engineering applications as 'gauge repeatability and reproducibility' [30, 31]. 1 We use cookies on our website to ensure you get the best experience. ^ k The algorithm has been developed to be used for the large amount of RCTs reporting KM curves. We therefore believe that the methods proposed here are likely to be the most accurate of the methods proposed so far, when at least numbers at risk or total events are reported. k d Guyot, P., Ades, A., Ouwens, M.J. et al. The number of patients at risk at each extracted co-ordinate, k, is then obtained by using Eq.1: where at the start of the interval we set e ^ The number of events, Each was reconstructed on two occasions by the same three observers. Williamson PR, Tudur Smith C, Hutton JL, Marson AG: Aggregate data meta-analysis with time-to-event outcomes. n =nris = NIH-funded researchers with TCGA complete an in-depth genomic analysis of 33 cancer types. censor times, ce Biometrika 1982 ; 69 : … 2007, 370 (9582): 143-52. Thus, if the original estimated survival was 50% we would expect any estimate to be 0.272% on either side (i.e. Whitehead A, Whitehead J: A general parametric approach to the meta-analysis of randomized clinical trials. Dear [4] extracts the survival probabilities and their variance and estimates their covariance using normal approximations under the assumption of no censoring. Example of reconstructed Kaplan-Meier curves. 727 patients were discharged. In published RCTs, there is generally no number at risk published at the end of the last interval, nint. This is due to the assumption of no censoring which was made in this case. This is an open access article distributed under the, Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. , and y-axis coordinates, S The intervals of KM estimates are designed to be such that at least one event occurs at the start of each interval, but this is not necessarily the case for our extracted co-ordinates, and so we need to track the time of the last event: where k' is such that Clinical Trials l 1995, 66: 133-152. In the 'neither' case, the ME became significantly negative, meaning that the uncertainty in the reconstructed HRs was underestimated. , evenly over interval i: The number of censored observations between extracted KM co-ordinates k and k + 1 is found by counting the number of estimated censor times, ce 2002, 25: 76-10.1177/0163278702025001006. https://doi.org/10.3390/cancers13030528, Conway, Caroline; Collins, Denis M.; McCann, Amanda; Dean, Kellie. , for k = 1,..., N points on the KM curve. n + You seem to have javascript disabled. ^ Rothman K, Greenland S, Lash TL: Modern epidemiology. I ^ u Cancers 2021, 13, 528. Medical decision Making. Hunink MGM, Wong JB: Meta-analysis of failure-time data with adjustment for covariates. Even if the arms are well balanced on a covariate, and even if the covariate is not an effect-modifier, aggregation over the covariate will tend to bias the treatment effect towards the null, and the extent of the bias increases with the strength of the covariate effect. , k+1: where Limitations of the new method should be mentioned. 1989, 25: 711-20. , at each extracted KM co-ordinate, k, and hence number of patients at risk at the next co-ordinate, , T The results of Randomized Controlled Trials (RCTs) on time-to-event outcomes that are usually reported are median time to events and Cox Hazard Ratio. The general principle of the algorithm is developed as well as solutions to some particular pitfalls that may be encountered in practical applications. In addition these reconstructed statistics were relatively insensitive to deterioration in the level of information used. The work was undertaken as part of a PhD studentship sponsored by Mapi Values, and was completed with funding from Medical Research Council grant G1001338. . Earle [10] provides a comparison of several methods [4, 23–25] by extracting the survival probabilities and estimating the number of patients at risk and number of events in successive time intervals by using the actuarial equations, using information on censoring if reported and ignoring censoring otherwise. "Research Strategies for Low-Survival Cancers" Cancers 13, no. Int J Technol Assess Health Care. ). Due to censoring, time-to-event outcomes are not amenable to standard statistical procedures used for analysis of continuous outcomes: the average survival time is a biased estimate of expected survival in the presence of censored observations. Because the p-value from the F-ratio test for the interaction was in all cases above 10%, we pooled the interaction term with the within-cell error term. k 10.1177/0272989X9401400108. The algorithm is implemented with the help of a few basic equations. + We have assumed that censoring occurs at a constant rate within each of the time intervals, which seems reasonable if the censoring pattern is non-informative (each subject has a censoring time that is statistically independent of their failure time). i Statistics in medicine. There is therefore no significant systematic error. k See further details. Access to the IPD, or to reconstructed data, allows a huge liberalization in modelling survival. 2000, 20: 104-111. T A simulation method was again used to obtain the 95% confidence intervals, which assumed that MEs were normally distributed. Patricia Guyot. Author to whom correspondence should be addressed. In most cases, it is clear that the information has been extracted from the curves [6–11], but only a few authors [8–10] report that they carry out the data extraction using digitizing software. n ; McCann, A.; Dean, K. Research Strategies for Low-Survival Cancers. This assumption is formally written in the equation below: STEP 7. ^ t In this case, we proceed as for the 'all information' case except that no re-adjustment using the total number of events can be done and we therefore stop at step 6. McDonald JB, Xub YJ: A generalization of the beta distribution with applications. Wang F-K, Li E: Confidence intervals in repeatability and reproducibility using the Bootstrap method. Google Scholar. for j = k' + 1,..., k - 1. k Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. This preliminary work needs to be performed carefully. 1 This ignores the direction of the errors and measures their magnitude, giving a measure of the absolute accuracy of the reconstructed outcomes. 1 , would be the number at risk at the beginning of interval i, multiplied by the probability of experiencing the event at interval i conditional on being alive at the beginning of interval i: Our initial guess for the number censored on interval i is the difference between the reported number at risk at the beginning of interval i + 1, nrisk : Advantages and disadvantages of systematic reviews using individual patient data. : The first input data file required for the algorithm contains the extracted x-axis coordinates, T o r Google Scholar, The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2288/12/9/prepub. As a response to the poor, limited, and inconsistent reporting of results from survival data, several authors have attempted to extract data from the published Kaplan-Meier (KM) curves in order to carry out meta-analysis [4–11]. If nrîs r 1 k , the time at which the number at risk is provided, trisk All these previous attempts reconstructed the data in the form of life-table data at a limited number of time points, whereas we have tried to reconstruct the original KM intervals. We begin by describing the algorithm for the case where the number at risk is reported at the start of the study and at least one other time-point and when the total number of events is reported ('all information' case). Stat Med.
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