Trial emulation and survival analysis for disease incidence registers: A case study on the causal effect of pre-emptive kidney transplantation

Stat Med. 2022 Sep 20;41(21):4176-4199. doi: 10.1002/sim.9503. Epub 2022 Jul 9.

Abstract

When drawing causal inference from observed data, failure time outcomes present additional challenges of censoring often combined with other missing data patterns. In this article, we follow incident cases of end-stage renal disease to examine the effect on all-cause mortality of starting treatment with transplant, so-called pre-emptive kidney transplantation, vs starting with dialysis possibly followed by delayed transplantation. The question is relatively simple: which start-off treatment is expected to bring the best survival for a target population? To address it, we emulate a target trial drawing on the long term Swedish Renal Registry, where a growing common set of baseline covariates was measured nationwide. Several lessons are learned which pertain to long term disease registers more generally. With characteristics of cases and versions of treatment evolving over time, informative censoring is already introduced in unadjusted Kaplan-Meier curves. This leads to misrepresented survival chances in observed treatment groups. The resulting biased treatment association may be aggravated upon implementing IPW for treatment. Aware of additional challenges, we further recall how similar studies to date have selected patients into treatment groups based on events occurring post treatment initiation. Our study reveals the dramatic impact of resulting immortal time bias combined with other typical features of long-term incident disease registers, including missing covariates during the early phases of the register. We discuss feasible ways of accommodating these features when targeting relevant estimands, and demonstrate how more than one causal question can be answered relying on the no unmeasured baseline confounders assumption.

Keywords: causal inference; disease registries; kidney transplantation; observational study; survival analysis; target trial emulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Incidence
  • Kidney Failure, Chronic* / epidemiology
  • Kidney Failure, Chronic* / surgery
  • Kidney Transplantation* / adverse effects
  • Registries
  • Renal Dialysis
  • Survival Analysis
  • Survival Rate