Multidisciplinary care and immortal time bias
Authors: Brenda R. Hemmelgarn, Jianguo Zhang, Braden J. Manns, Marcello Tonelli
Journal: Kidney International (2013)

To the Editor: We read with interest the article by Liu et al.1.Liu J. Weinhandl E.D. Gilbertson D.T. et al.Issues regarding ‘immortal time’ in the analysis of the treatment effects in observational studies.Kidney Int. 2012; 81: 341-350Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar Similar to an earlier article by Shariff et al.,2.Shariff S. Cuerden M.S. Jain A.K. et al.The secret of immortal time bias in epidemiologic studies.J Am Soc Nephrol. 2008; 19: 841-843Crossref PubMed Scopus (131) Google Scholar this article suggested that the noted association between multidisciplinary care (MDC) and better survival that we reported for patients with chronic kidney disease3.Hemmelgarn B.R. Manns B.J. Zhang J. et al.Association between multidisciplinary care and survival for elderly patients with chronic kidney disease.J Am Soc Nephrol. 2007; 18: 993-999Crossref PubMed Scopus (141) Google Scholar was due to immortal time bias. This bias occurs when the exposure of interest occurs sometime after entering the study cohort—specifically, in cases where individuals must survive longer to be eligible for entry into the ‘exposure’ group (in this instance MDC), but where there are no minimal survival requirements for those in the unexposed group (no MDC care).4.Walker A.M. Observation and Inference: An Introduction to the Methods of Epidemiology. Epidemiology Resources Inc, Newton Lower Falls, MA1991Google Scholar,5.Rothman K.J. Greenland S. Modern Epidemiology. 2nd edn. Lippincott-Raven, Philadelphia, PA1998Google Scholar Liu et al.1.Liu J. Weinhandl E.D. Gilbertson D.T. et al.Issues regarding ‘immortal time’ in the analysis of the treatment effects in observational studies.Kidney Int. 2012; 81: 341-350Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar propose that patients in the MDC group may have been subject to ‘immortal time’ in that their entry into the cohort was defined based on a serum creatinine measurement between 1 July and 31 December 2001, with exposure (MDC care) defined by a clinic visit between 1 July 2001 and 31 December 2002. Thus, patients with a serum creatinine measurement (at cohort entry and time zero) before their MDC visit have a period of ‘immortal time,’ as they must have survived to the time of their MDC visit to be eligible for enrollment. The same period of potential immortal time is not available to the unexposed group (no MDC care). Although theoretically there is a potential for the bias, the context in which this is applied must also be considered. As they did not have access to our data set, we were puzzled to read the statement by Liu et al.1.Liu J. Weinhandl E.D. Gilbertson D.T. et al.Issues regarding ‘immortal time’ in the analysis of the treatment effects in observational studies.Kidney Int. 2012; 81: 341-350Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar that ‘much of the protective effect (of MDC) can be attributed to immortal time being mistakenly assigned to the multidisciplinary care patients.’ This unsupported assertion (like the similar assertion made by Shariff et al.2.Shariff S. Cuerden M.S. Jain A.K. et al.The secret of immortal time bias in epidemiologic studies.J Am Soc Nephrol. 2008; 19: 841-843Crossref PubMed Scopus (131) Google Scholar) is incorrect. Liu et al.1.Liu J. Weinhandl E.D. Gilbertson D.T. et al.Issues regarding ‘immortal time’ in the analysis of the treatment effects in observational studies.Kidney Int. 2012; 81: 341-350Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar and Shariff et al.2.Shariff S. Cuerden M.S. Jain A.K. et al.The secret of immortal time bias in epidemiologic studies.J Am Soc Nephrol. 2008; 19: 841-843Crossref PubMed Scopus (131) Google Scholar both suggested two possible methods to account for potential immortal time bias within our study, namely matching at the design stage and the use of a time-dependent covariate for exposure definition, and we have re-analyzed our data accordingly. As shown in Table 1, the association between receipt of MDC care and lower mortality persisted regardless of the method used.Table 1Hazard ratios of death for MDC care compared with no MDC care, based on initial published results, and re-analysis using matching at the design stage and using a time-dependent exposure definitionUnadjusted hazard ratio (95% CI)AdjustedaFor age, gender, baseline estimated glomerular filtration rate, diabetes, and comorbidity score. hazard ratio (95% CI)Results as published0.56 (0.40–0.79)0.50 (0.35–0.71)Using matching at design stage0.65 (0.46–0.93)0.56 (0.39–0.81)Using time-dependent exposure0.67 (0.47–0.94)0.58 (0.41–0.83)Abbreviations: CI, confidence interval; MDC, multidisciplinary care.a For age, gender, baseline estimated glomerular filtration rate, diabetes, and comorbidity score. Open table in a new tab Abbreviations: CI, confidence interval; MDC, multidisciplinary care. Thus, although we agree with Liu et al.1.Liu J. Weinhandl E.D. Gilbertson D.T. et al.Issues regarding ‘immortal time’ in the analysis of the treatment effects in observational studies.Kidney Int. 2012; 81: 341-350Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar that immortal time bias is an important consideration for studies of this type, we disagree that this type of bias has accounted for much of the observed survival benefit of MDC. However, as we previously emphasized,3.Hemmelgarn B.R. Manns B.J. Zhang J. et al.Association between multidisciplinary care and survival for elderly patients with chronic kidney disease.J Am Soc Nephrol. 2007; 18: 993-999Crossref PubMed Scopus (141) Google Scholar the true impact of MDC care on patient survival can only be confirmed by a well-designed randomized trial.