Development of a prognostic model of respiratory insufficiency or death in amyotrophic lateral sclerosis

Abstract

A clinically useful model to prognose onset of respiratory insufficiency in amyotrophic lateral sclerosis (ALS) would inform disease interventions, communication and clinical trial design. We aimed to derive and validate a clinical prognostic model for respiratory insufficiency within 6 months of presentation to an outpatient ALS clinic.We used multivariable logistic regression and internal cross-validation to derive a clinical prognostic model using a single-centre cohort of 765 ALS patients who presented between 2006 and 2015. External validation was performed using the multicentre Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database with 7083 ALS patients. Predictors included baseline characteristics at first outpatient visit. The primary outcome was respiratory insufficiency within 6 months, defined by initiation of noninvasive ventilation, forced vital capacity (FVC) <50% predicted, tracheostomy, or death.Of 765 patients in our centre, 300 (39%) had respiratory insufficiency or death within 6 months. Six baseline characteristics (diagnosis age, delay between symptom onset and diagnosis, FVC, symptom onset site, amyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-R) total score and ALSFRS-R dyspnoea score) were used to prognose the risk of the primary outcome. The derivation cohort c-statistic was 0.86 (95% CI 0.84-0.89) and internal cross-validation produced a c-statistic of 0.86 (95% CI 0.85-0.87). External validation of the model using the PRO-ACT cohort produced a c-statistic of 0.74 (95% CI 0.72-0.75).We derived and externally validated a clinical prognostic rule for respiratory insufficiency in ALS. Future studies should investigate interventions on equivalent high-risk patients.

Figure 1

a) Receiver operating characteristic curve for prognosis of respiratory insufficiency (including death) within 6 months in the Penn cohort. b) Kaplan–Meier curves with 95% confidence intervals stratified by prognostic probability of respiratory insufficiency in the Penn cohort, truncated at 180 days.

Figure 2

a) Receiver operating characteristic curves for derivation and external validation of respiratory insufficiency within 6 months (test of equality, p<0.001). b) Kaplan–Meier curves with 95% confidence intervals stratified by prognostic probability of respiratory insufficiency in the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) cohort, truncated at 180 days.