title: Analysis of amyotrophic lateral sclerosis as a multistep process: a population-based modelling study.
abstract: BACKGROUND
  Amyotrophic lateral sclerosis shares characteristics with some cancers, such as onset being more common in later life, progression usually being rapid, the disease affecting a particular cell type, and showing complex inheritance. We used a model originally applied to cancer epidemiology to investigate the hypothesis that amyotrophic lateral sclerosis is a multistep process.
  
  
  METHODS
  We generated incidence data by age and sex from amyotrophic lateral sclerosis population registers in Ireland (registration dates 1995-2012), the Netherlands (2006-12), Italy (1995-2004), Scotland (1989-98), and England (2002-09), and calculated age and sex-adjusted incidences for each register. We regressed the log of age-specific incidence against the log of age with least squares regression. We did the analyses within each register, and also did a combined analysis, adjusting for register.
  
  
  RESULTS
  We identified 6274 cases of amyotrophic lateral sclerosis from a catchment population of about 34 million people. We noted a linear relationship between log incidence and log age in all five registers: England r(2)=0·95, Ireland r(2)=0·99, Italy r(2)=0·95, the Netherlands r(2)=0·99, and Scotland r(2)=0·97; overall r(2)=0·99. All five registers gave similar estimates of the linear slope ranging from 4·5 to 5·1, with overlapping confidence intervals. The combination of all five registers gave an overall slope of 4·8 (95% CI 4·5-5·0), with similar estimates for men (4·6, 4·3-4·9) and women (5·0, 4·5-5·5).
  
  
  CONCLUSIONS
  A linear relationship between the log incidence and log age of onset of amyotrophic lateral sclerosis is consistent with a multistage model of disease. The slope estimate suggests that amyotrophic lateral sclerosis is a six-step process. Identification of these steps could lead to preventive and therapeutic avenues.
  
  
  BACKGROUND
  UK Medical Research Council; UK Economic and Social Research Council; Ireland Health Research Board; The Netherlands Organisation for Health Research and Development (ZonMw); the Ministry of Health and Ministry of Education, University, and Research in Italy; the Motor Neurone Disease Association of England, Wales, and Northern Ireland; and the European Commission (Seventh Framework Programme).
authors.affiliation: King's College London, Institute of Psychiatry, Department of Clinical Neuroscience, London, UK. Electronic address: ammar.al-chalabi@kcl.ac.uk.
authors.forename: Ammar
authors.initials: A
authors.lastname: Al-Chalabi
authors.affiliation: ALS Center, Rita Levi Montalcini Department of Neuroscience, University of Turin, Turin, Italy; Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy; Neuroscience Institute of Turin (NIT), Turin, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Calvo
authors.affiliation: ALS Center, Rita Levi Montalcini Department of Neuroscience, University of Turin, Turin, Italy; Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy; Neuroscience Institute of Turin (NIT), Turin, Italy.
authors.forename: Adriano
authors.initials: A
authors.lastname: Chio
authors.affiliation: Euan MacDonald Centre for MND Research, University of Edinburgh, Edinburgh, UK.
authors.forename: Shuna
authors.initials: S
authors.lastname: Colville
authors.affiliation: Motor Nerve Clinic, King's College Hospital, London, UK.
authors.forename: Cathy M
authors.initials: CM
authors.lastname: Ellis
authors.affiliation: Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors.forename: Orla
authors.initials: O
authors.lastname: Hardiman
authors.affiliation: Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors.forename: Mark
authors.initials: M
authors.lastname: Heverin
authors.affiliation: Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK; National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Robin S
authors.initials: RS
authors.lastname: Howard
authors.affiliation: Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, Netherlands.
authors.forename: Mark H B
authors.initials: MHB
authors.lastname: Huisman
authors.affiliation: King's College London, Institute of Psychiatry, Department of Clinical Neuroscience, London, UK.
authors.forename: Noa
authors.initials: N
authors.lastname: Keren
authors.affiliation: Department of Neurology, Brighton and Sussex Medical School Trafford Centre for Biomedical Research, University of Sussex, Falmer, East Sussex, UK.
authors.forename: P Nigel
authors.initials: PN
authors.lastname: Leigh
authors.affiliation: Department of Neurology, 'Amedeo Avogadro' University of Eastern Piedmont and Azienda Ospedaliera Universitaria Maggiore della Carità, Novara, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Mazzini
authors.affiliation: Salvatore Maugeri Foundation, IRCSS; Scientific Institute of Milan, Milan, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Mora
authors.affiliation: Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK; National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Orrell
authors.affiliation: Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors.forename: James
authors.initials: J
authors.lastname: Rooney
authors.affiliation: Department of Neurology, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Kirsten M
authors.initials: KM
authors.lastname: Scott
authors.affiliation: King's College London, Institute of Psychiatry, Department of Clinical Neuroscience, London, UK.
authors.forename: William J
authors.initials: WJ
authors.lastname: Scotton
authors.affiliation: Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, Netherlands.
authors.forename: Meinie
authors.initials: M
authors.lastname: Seelen
authors.affiliation: King's College London, Institute of Psychiatry, Department of Clinical Neuroscience, London, UK.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
authors.affiliation: Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK; National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Katie S
authors.initials: KS
authors.lastname: Sidle
authors.affiliation: Euan MacDonald Centre for MND Research, University of Edinburgh, Edinburgh, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Swingler
authors.affiliation: King's College London, Institute of Psychiatry, Department of Clinical Neuroscience, London, UK.
authors.forename: Miho
authors.initials: M
authors.lastname: Tsuda
authors.affiliation: Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, Netherlands.
authors.forename: Jan H
authors.initials: JH
authors.lastname: Veldink
authors.affiliation: Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, Netherlands.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Visser
authors.affiliation: Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, Netherlands.
authors.forename: Leonard H
authors.initials: LH
authors.lastname: van den Berg
authors.affiliation: Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, UK; Centre for Public Health Research, Massey University Wellington Campus, Wellington, New Zealand.
authors.forename: Neil
authors.initials: N
authors.lastname: Pearce
mesh_terms: D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis / Q000453:epidemiology*; D018450:Disease Progression; D004739:England / Q000453:epidemiology; D005260:Female; D005387:Finland / Q000453:epidemiology; D006801:Humans; D007494:Ireland / Q000453:epidemiology; D007558:Italy / Q000453:epidemiology; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D008962:Models, Theoretical; D011159:Population Surveillance / Q000379:methods*; D012042:Registries / Q000706:statistics & numerical data; D012606:Scotland / Q000453:epidemiology