title: The MITOS system predicts long-term survival in amyotrophic lateral sclerosis.
abstract: OBJECTIVE
  The choice of adequate proxy for long-term survival, the ultimate outcome in randomised clinical trials (RCT) assessing disease-modifying treatments for amyotrophic lateral sclerosis (ALS), is a key issue. The intrinsic limitations of the ALS Functional Rating Scale-Revised (ALSFRS-R), including non-linearity, multidimensionality and floor-effect, have emerged and its usefulness argued. The ALS Milano-Torino staging (ALS-MITOS) system was proposed as a novel tool to measure the progression of ALS and overcome these limitations. This study was performed to validate the ALS-MITOS as a 6-month proxy of survival in 200 ALS patients followed up to 18 months.
  
  
  METHODS
  Analyses were performed on data from the recombinant human erythropoietin RCT that failed to demonstrate differences between groups for both primary and secondary outcomes. The ALS-MITOS system is composed of four key domains included in the ALSFRS-R scale (walking/self-care, swallowing, communicating and breathing), each with a threshold reflecting the loss of function in the specific ALSFRS-R subscores. Sensitivity, specificity and the area under the curve of the receiver operating characteristic curves of the ALS-MITOS system stages and ALSFRS-R decline at 6 months were calculated and compared with the primary outcome (survival, tracheotomy or >23-hour non-invasive ventilation) at 12 and 18 months Predicted probabilities of the ALS-MITO system at 6 months for any event at 12 and 18 months were computed through logistic regression models.
  
  
  RESULTS
  Disease progression from baseline to 6 months as defined by the ALS-MITOS system predicted death, tracheotomy or >23-hour non-invasive ventilation at 12 months with 82% sensitivity (95% CI 71% to 93%, n=37/45) and 63% specificity (95% CI 55% to 71%, n=92/146), and at 18 months with 71% sensitivity (95% CI 61% to 82%, n=50/70) and 68% specificity (95% CI 60% to 77%, n=76/111). The analysis of ALS-MITOS and ALSFRS-R progression at 6-month follow-up showed that the best cut-off to predict survival at 12 and 18 months was 1 for the ALS-MITOS (ie, loss of at least one function) and a decline ranging from 6 to 9 points for the ALSFRS-R.
  
  
  CONCLUSIONS
  The ALS-MITOS system can reliably predict the course of ALS up to 18 months and can be considered a novel and valid outcome measure in RCTs.
authors.affiliation: Neuroepidemiology Unit, IRCCS Foundation, "Carlo Besta" Neurological Institute, Milan, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Tramacere
authors.affiliation: 3rd Neurology Unit, Motor Neuron Diseases Centre, IRCCS Foundation, "Carlo Besta" Neurological Institute, Milan, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Dalla Bella
authors.affiliation: Department of Neurosciences, ALS Centre, "Rita Levi Montalcini", University of Turin and Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Turin, Italy.
authors.forename: Adriano
authors.initials: A
authors.lastname: Chiò
authors.affiliation: IRCCS "Salvatore Maugeri" Foundation, Milan, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Mora
authors.affiliation: Neuroepidemiology Unit, IRCCS Foundation, "Carlo Besta" Neurological Institute, Milan, Italy.
authors.forename: Graziella
authors.initials: G
authors.lastname: Filippini
authors.affiliation: 3rd Neurology Unit, Motor Neuron Diseases Centre, IRCCS Foundation, "Carlo Besta" Neurological Institute, Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lauria
mesh_terms: D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis* / Q000473:pathology; D003142:Communication; D003679:Deglutition; D004185:Disability Evaluation; D018450:Disease Progression; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D063087:Noninvasive Ventilation; D011237:Predictive Value of Tests; D012372:ROC Curve; D012119:Respiration; D012648:Self Care; D016019:Survival Analysis; D016138:Walking
keywords: ALS; MOTOR NEURON DISEASE; NEUROMUSCULAR; RANDOMISED TRIALS