1. The analysis of survival data: the Kaplan Meier method Kitty J. Jager¹, Paul van Dijk 1,2, Carmine Zoccali 3 and Friedo W. Dekker 1,4 1 ERA–EDTA Registry, Dept. of Medical Informatics, Academic Medical Center, Amsterdam, The Netherlands 2 Department of Clinical Epidemiology, Biostatistics and Bio-informatics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands 3 CNR–IBIM Clinical Epidemiology and Pathophysiology of Renal Diseases and Hypertension, Renal and Transplantation Unit, Ospedali Riuniti, 89125 Reggio Cal., Italy 4 Department of Clinical Epidemiology, Leiden University Medical Centre, Leiden, The Netherlands Kidney International: ABC on epidemiology

2. Survival analysis Aim: modeling and analysis of time-to-event data Events may include all kinds of positive or negative events Single and combined endpoints This presentation includes a first introduction to survival analysis techniques

3. Events versus censored data At the end of the follow-up period the event will probably not have occurred for all patients. For those patients survival time is censored. Censoring: we do not know when or whether such a patient will experience the event of interest, only that he or she has not done so by the end of the observation period. Censoring occurs at the end of the observation period, at loss to follow-up or at the occurrence of a competing event. Example 1 – Survival time on RRT: events and censored observations. Incident RRT patients in the ERA-EDTA Registry were included in an analysis of patient survival on RRT. Like in most survival studies patients were recruited over a period of time (1996-2000 - the inclusion period) and they were observed up to a specific date (31 December 2005 - the end of the follow-up period). During this period the event of interest was death while on RRT, whereas censoring took place at recovery of renal function, loss to follow-up and at 31 December 2005.

4. The incidence rate of death Figure: Survival times of eight patients at risk of death on RRT. The inclusion period was 1996-2000, whereas follow-up was ended on 31 December 2005.

5. Assumptions related to censoring At any time patients who are censored have the same survival prospects as those who continue to be followed. –This sometimes is problematic: e.g. in the calculation of survival on dialysis censoring at the time of transplantation is needed because these patients are no longer at risk of death on dialysis – however dialysis patients on the transplant waiting list do not have the same prospects as dialysis patients who are not on the waiting list Survival probabilities are assumed to be the same for subjects recruited early and late in the study. –May test this by splitting a cohort of patients in those who were recruited early and those recruited late and see if their survival curves are different.

6. Kaplan Meier method Observed survival times were first sorted in ascending order, starting with the patient with the shortest survival time and presented in a table. Example 2 - Survival probability in RRT patients due to diabetes mellitus and other causes In a sample of 50 RRT patients taken from a study on diabetes mellitus survival time started running at the moment a patient was included in the study, in this case at the start of RRT. Patients were followed until death or censoring. The survival probability was calculated using the Kaplan Meier method. Subsequently, the survival of patients with ESRD due to diabetes mellitus was compared to the survival of those with ESRD due to other causes. Used to estimate survival probabilities and to compare survival of different groups.

7. Kaplan Meier method At the start of the study all 50 patients were alive - proportion surviving and cumulative survival were 1.00 When the first patient died on day 34 after the start of RRT, the proportion surviving was 49/50 = 0.9800 = 98%. To calculate the cumulative survival this proportion surviving was multiplied by the 1.0 cumulative survival from the previous step resulting in a cumulative survival dropping to 0.9800. When the second patient died at day 35, the proportion surviving was 48/49 = 0.9796. To obtain the cumulative survival at day 35, again, this proportion was multiplied by the 0.9800 cumulative survival from the previous step which resulted in a cumulative survival dropping that day to 0.9600. On day 57, however, a patient was withdrawn alive from the study (censored). The proportion surviving that day was 47/47 = 1.00, as this patient did not die but was withdrawn alive from the study. As a result the cumulative survival did not drop that day but remained unchanged at 0.9400. Time in days Number at risk DeathsWithdrawn alive (censored) Proportion surviving on this day Cumulative survival Cumulative mortality 050001.00 0 34501049/50 = 0.98000.98000.0200 35491048/49 = 0.97960.96000.0400 44481047/48 = 0.97920.94000.0600 57470110.94000.0600 …....

8. Kaplan Meier method Cumulative survival is a probability of surviving the next period multiplied by the probability of having survived the previous period All subjects at risk - also those not experiencing the event during the observation period - can contribute survival time to the denominator of the incidence rate By censoring one is able to reduce the number of persons alive without affecting the cumulative survival

9. Kaplan Meier method The median survival is that point in time, from the time of inclusion, when the cumulative survival drops below 50%, in this case it is 1708 days Is not related to the number of deaths or the number of subjects that is still at risk Why mean survival is used less frequently: –Survival data mostly highly skewed –In case of censoring one does not know if and when the person will experience the event – this complicates the calculation of the mean –In order to calculate a mean survival one would need to wait until all persons experienced the event Time in days Number at risk DeathsWithdrawn alive (censored) Proportion surviving on this day Cumulative survival Cumulative mortality 050001.00 0 34501049/50 = 0.98000.98000.0200 35491048/49 = 0.97960.96000.0400 44481047/48 = 0.97920.94000.0600 57470110.94000.0600 ….... 1650181017/18 = 0.94440.52890.4711 1708171016/17 = 0.94120.49780.5022

10. Logrank test Most popular method of comparing the survival of groups Takes the whole follow-up period into account Addresses the hypothesis that there are no differences between the populations being studied in the probability of an event at any time point P = 0.04

11. What the Kaplan Meier method and the logrank test can and cannot do Together the Kaplan Meier method and the logrank test provide an opportunity to: –Estimate survival probabilities and –Compare survival between groups However –One cannot adjust for confounding variables – no mutlivariate analysis –They do not provide an estimate of the effect size and the relating confidence interval In those cases one needs a regression technique like the Cox proportional hazards model