Abstract
IntroductionThe 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.MethodsWe 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.ResultsOn 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).DiscussionOur 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.
Highlights
The Irish Amyotrophic Lateral Sclerosis (ALS) register is a valuable resource for examining survival factors in Irish ALS patients
A recent prospective study from our group has found that the presence of executive dysfunction (HR 3.44 95% CI: 1.45–8.18) or fronto-temporal dementia (FTD) (HR 2.67 95% CI: 1.04–6.85) in incident Irish ALS patients is significantly associated with a poorer prognosis [4]
Data Sources The Irish ALS register was established in 1995 to follow incident ALS patients over time using multiple independent data sources and capture-recapture methodology [2]. This analysis includes data on patients diagnosed between 1st of January 1995 and 31st December 2010 from the register, augmented with data on riluzole prescription obtained from the Health Services Executive of Ireland (HSE), data on the prescription of NIV obtained from the NIV systems supplier, and gastrostomy insertion data from hospital records to compile our final data set
Summary
The Irish ALS register is a valuable resource for examining survival factors in Irish ALS patients. With an incidence in Europe of 2–3 people per 100,000 of population [1], large nationalized disease registries such as the Irish ALS register [2] prospectively collecting patients over a long period are necessary to fully appreciate the diverse clinical features of the condition. A systematic review of ALS survival found that both bulbar onset disease and El-Escorial criteria definite disease have been associated with a significantly poorer prognosis [3]. A recent prospective study from our group has found that the presence of executive dysfunction (HR 3.44 95% CI: 1.45–8.18) or fronto-temporal dementia (FTD) (HR 2.67 95% CI: 1.04–6.85) in incident Irish ALS patients is significantly associated with a poorer prognosis [4]
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