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.

Findings: 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).

Interpretation: 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.

Funding: 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).

Figure 1

Log(incidence) vs log(age) for the five registers combined The fit to a straight line is good (r²=0·99), consistent with a multistep model.

Figure 2

Forest plot of the estimates of n–1 from each register and overall in all age groups with a weighted average across registers All registers had results consistent with a slope (n–1) estimate of 5, and the meta-analysis showed little evidence of heterogeneity. The weights of each study shown by the size of the grey squares are England 7·0%, Ireland 38·0%, Italy 9·8%, the Netherlands 34·4%, and Scotland 10·8%. The black diamonds show the estimate of n–1, with the bars representing the 95% CI.

Figure 3

Log(incidence) vs log(age) for multiple sclerosis Data from the Manitoba register. The line is not straight, showing that the disease process does not fit to a multistep model.