Survival analysis of irish amyotrophic lateral sclerosis patients diagnosed from 1995-2010

PLoS One. 2013 Sep 30;8(9):e74733. doi: 10.1371/journal.pone.0074733. eCollection 2013.


Introduction: The Irish ALS register is a valuable resource for examining survival factors in Irish ALS patients. Cox regression has become the default tool for survival analysis, but recently new classes of flexible parametric survival analysis tools known as Royston-Parmar models have become available.

Methods: We employed Cox proportional hazards and Royston-Parmar flexible parametric modeling to examine factors affecting survival in Irish ALS patients. We further examined the effect of choice of timescale on Cox models and the proportional hazards assumption, and extended both Cox and Royston-Parmar models with time varying components.

Results: On comparison of models we chose a Royston-Parmar proportional hazards model without time varying covariates as the best fit. Using this model we confirmed the association of known survival markers in ALS including age at diagnosis (Hazard Ratio (HR) 1.34 per 10 year increase; 95% CI 1.26-1.42), diagnostic delay (HR 0.96 per 12 weeks delay; 95% CI 0.94-0.97), Definite ALS (HR 1.47 95% CI 1.17-1.84), bulbar onset disease (HR 1.58 95% CI 1.33-1.87), riluzole use (HR 0.72 95% CI 0.61-0.85) and attendance at an ALS clinic (HR 0.74 95% CI 0.64-0.86).

Discussion: Our analysis explored the strengths and weaknesses of Cox proportional hazard and Royston-Parmar flexible parametric methods. By including time varying components we were able to gain deeper understanding of the dataset. Variation in survival between time periods appears to be due to missing data in the first time period. The use of age as timescale to account for confounding by age resolved breaches of the proportional hazards assumption, but in doing so may have obscured deficiencies in the data. Our study demonstrates the need to test for, and fully explore, breaches of the Cox proportional hazards assumption. Royston-Parmar flexible parametric modeling proved a powerful method for achieving this.

Publication types

  • Comparative Study
  • Evaluation Study
  • Historical Article
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Amyotrophic Lateral Sclerosis / epidemiology*
  • Amyotrophic Lateral Sclerosis / history
  • History, 20th Century
  • History, 21st Century
  • Humans
  • Ireland / epidemiology
  • Proportional Hazards Models
  • Survival Analysis
  • Time Factors

Grant support

Funding is from Health Seventh Framework Programme (FP7/2007–2013) under grant agreement n° 259867, ALSA (the ALS Association), HRB (the Health Research Board, grant H01300), Joint Programme in Neurodegeneration and Research Motor Neuron (previously named Motor Neuron Disease Research Foundation). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.