James Rooney

Analysis of amyotrophic lateral sclerosis as a multistep process: a population-based modelling study

Summary 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 r2=0·95, Ireland r2=0·99, Italy r2=0·95, the Netherlands r2=0·99, and Scotland r2=0·97; overall r2=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).

A multidisciplinary clinic approach improves survival in ALS: a comparative study of ALS in Ireland and Northern Ireland

Background Amyotrophic lateral sclerosis (ALS) is a progressive debilitating neurodegenerative disease, with a life expectancy of 3–5 years from first symptom. There is compelling evidence that those who attend a multidisciplinary clinic experience improved survival. The purpose of the study was to explore the survival of patients with ALS ascertained through population-based Registers in the Republic of Ireland (RoI) and Northern Ireland (NI), and to determine whether centralisation of services confers advantage compared with community-based care supported by a specialist care worker. Methods The island of Ireland is divided into two countries, RoI and NI, each with an independent healthcare system. Both countries have population-based ALS Registers with full ascertainment. Data from all 719 incident ALS cases from Ireland and NI, diagnosed between 1 January 2005 and 31 December 2010, were used in the analysis. Results A survival benefit was identified for patients who attended the multidisciplinary ALS clinic in the RoI. (HR 0.59, 95% CI 0.49 to 0.71, p<0.001). This difference was preserved following multivariate analysis. A trend towards improved survival was noted for patients with ALS from NI when compared with RoI patients who did not attend a multidisciplinary clinic. Conclusions Centralised multidisciplinary care confers a survival advantage for patients with ALS and is superior to devolved community-based care. We propose that multiple decision-making processes within a multidisciplinary setting lead to an enriched set of clinical encounters for the patient and carer that enhances clinical outcome.

Survival Analysis of Irish Amyotrophic Lateral Sclerosis Patients Diagnosed from 1995–2010

Introduction The 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. Methods We 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. Results On 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). Discussion Our 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.

The retention time of inorganic mercury in the brain — A systematic review of the evidence

Reports from human case studies indicate a half-life for inorganic mercury in the brain in the order of years-contradicting older radioisotope studies that estimated half-lives in the order of weeks to months in duration. This study systematically reviews available evidence on the retention time of inorganic mercury in humans and primates to better understand this conflicting evidence. A broad search strategy was used to capture 16,539 abstracts on the Pubmed database. Abstracts were screened to include only study types containing relevant information. 131 studies of interest were identified. Only 1 primate study made a numeric estimate for the half-life of inorganic mercury (227-540 days). Eighteen human mercury poisoning cases were followed up long term including autopsy. Brain inorganic mercury concentrations at death were consistent with a half-life of several years or longer. 5 radionucleotide studies were found, one of which estimated head half-life (21 days). This estimate has sometimes been misinterpreted to be equivalent to brain half-life-which ignores several confounding factors including limited radioactive half-life and radioactive decay from surrounding tissues including circulating blood. No autopsy cohort study estimated a half-life for inorganic mercury, although some noted bioaccumulation of brain mercury with age. Modelling studies provided some extreme estimates (69 days vs 22 years). Estimates from modelling studies appear sensitive to model assumptions, however predications based on a long half-life (27.4 years) are consistent with autopsy findings. In summary, shorter estimates of half-life are not supported by evidence from animal studies, human case studies, or modelling studies based on appropriate assumptions. Evidence from such studies point to a half-life of inorganic mercury in human brains of several years to several decades. This finding carries important implications for pharmcokinetic modelling of mercury and potentially for the regulatory toxicology of mercury.

Association of a locus in the CAMTA1 gene with survival in patients with sporadic amyotrophic lateral sclerosis

IMPORTANCE Amyotrophic lateral sclerosis (ALS) is a devastating adult-onset neurodegenerative disorder with a poor prognosis and a median survival of 3 years. However, a significant proportion of patients survive more than 10 years from symptom onset. OBJECTIVE To identify gene variants influencing survival in ALS. DESIGN, SETTING, AND PARTICIPANTS This genome-wide association study (GWAS) analyzed survival in data sets from several European countries and the United States that were collected by the Italian Consortium for the Genetics of ALS and the International Consortium on Amyotrophic Lateral Sclerosis Genetics. The study population included 4256 patients with ALS (3125 [73.4%] deceased) with genotype data extended to 7 174 392 variants by imputation analysis. Samples of DNA were collected from January 1, 1993, to December 31, 2009, and analyzed from March 1, 2014, to February 28, 2015. MAIN OUTCOMES AND MEASURES Cox proportional hazards regression under an additive model with adjustment for age at onset, sex, and the first 4 principal components of ancestry, followed by meta-analysis, were used to analyze data. Survival distributions for the most associated genetic variants were assessed by Kaplan-Meier analysis. RESULTS Among the 4256 patients included in the analysis (2589 male [60.8%] and 1667 female [39.2%]; mean [SD] age at onset, 59 [12] years), the following 2 novel loci were significantly associated with ALS survival: at 10q23 (rs139550538; P = 1.87 × 10-9) and in the CAMTA1 gene at 1p36 (rs2412208, P = 3.53 × 10-8). At locus 10q23, the adjusted hazard ratio for patients with the rs139550538 AA or AT genotype was 1.61 (95% CI, 1.38-1.89; P = 1.87 × 10-9), corresponding to an 8-month reduction in survival compared with TT carriers. For rs2412208 CAMTA1, the adjusted hazard ratio for patients with the GG or GT genotype was 1.17 (95% CI, 1.11-1.24; P = 3.53 × 10-8), corresponding to a 4-month reduction in survival compared with TT carriers. CONCLUSIONS AND RELEVANCE This GWAS robustly identified 2 loci at genome-wide levels of significance that influence survival in patients with ALS. Because ALS is a rare disease and prevention is not feasible, treatment that modifies survival is the most realistic strategy. Therefore, identification of modifier genes that might influence ALS survival could improve the understanding of the biology of the disease and suggest biological targets for pharmaceutical intervention. In addition, genetic risk scores for survival could be used as an adjunct to clinical trials to account for the genetic contribution to survival.

What does the ALSFRS-R really measure? A longitudinal and survival analysis of functional dimension subscores in amyotrophic lateral sclerosis.

Introduction ALS functional rating scale (revised) (ALSFRS-R) is the most widely used functional rating system in patients with amyotrophic lateral sclerosis (ALS). However, heterogeneity in ALSFRS-R progression renders analysis challenging. We have explored the characteristics of total ALSFRS-R, and ALSFRS-R subscores in longitudinal and survival models, to determine whether subscore analysis enhances the precision of the instrument. Methods All cases with ALSFRS-R scores on the Irish ALS register were included. ALSFRS-R subscores were defined for bulbar, motor and respiratory domains. Longitudinal models were used to visualise fitted total ALSFRS-R and ALSFRS-R subscore progression. In addition, the prognostic value of convenience and computed ALSFRS-R slope and subscore slopes were compared. Results 407 incident cases were identified with a complete ALSFRS-R measure. 233 (57%) patients were male, and 125 (31%) had bulbar-onset disease. ALSFRS-R bulbar and motor subscore slopes provided a better fit in prognostic models when combined over the total ALSFRS-R slope. Longitudinal analysis revealed that the ALSFRS-R motor subscore deteriorated earlier in spinal-onset disease over bulbar-onset disease, while in bulbar-onset disease the ALSFRS-R bulbar subscore deteriorated earlier and faster than in spinal-onset disease. Discussion Our analysis builds on previous knowledge of ALSFRS-R subscores. Decline in ALSFRS-R motor subscores in patients with spinal-onset disease, and decline in ALSFRS-R bulbar subscores in patients with bulbar-onset disease, may predate reported disease onset dates. Respiratory subscores were not prognostically informative after adjustment for bulbar and motor subscores. These results provide robust evidence that the ALSFRS-R should not be reported as a single combined score, but rather as domain specific subscores.

The changing picture of amyotrophic lateral sclerosis: lessons from European registers

Prospective population based-registers of amyotrophic lateral sclerosis (ALS) have operated in Europe for over two decades, and have provided important insights into our understanding of ALS. Here, we review the benefits that population registers have brought to the understanding of the incidence, prevalence, phenotype and genetics of ALS and outline the core operating principles that underlie these registers and facilitate international collaboration. Going forward, we offer lessons learned from our collective experience of operating population-based ALS registers in Europe for over two decades, focusing on register design, maintenance, identification and management of bias and the value of cross-national harmonisation and integration.

Spatial cluster analysis of population amyotrophic lateral sclerosis risk in Ireland

Editors’ Note: In WriteClick this week, Drs. Finke and Prüss comment on influenza-associated encephalitis (IAE) as discussed in “Clinical Reasoning: A 57-year-old woman who developed acute amnesia following fever and upper respiratory symptoms,” and suggest patients with suspected IAE be tested for neuronal antibodies. In reference to “Spatial cluster analysis of population amyotrophic lateral sclerosis risk in Ireland,” Drs. Bradley et al. and authors Rooney et al., who have published further work, discuss methodologic considerations in testing for amyotrophic lateral sclerosis clusters. —Megan Alcauskas, MD, and Robert C. Griggs, MD

Benefits, pitfalls, and future design of population-based registers in neurodegenerative disease

Population-based disease registers identify and characterize all cases of disease, including those that might otherwise be neglected. Prospective population-based registers in neurodegeneration are necessary to provide comprehensive data on the whole phenotypic spectrum and can guide planning of health services. With the exception of the rare disease amyotrophic lateral sclerosis, few complete population-based registers exist for neurodegenerative conditions. Incomplete ascertainment, limitations and uncertainty in diagnostic categorization, and failure to recognize sources of bias reduce the accuracy and usefulness of many registers. Common biases include population stratification, the use of prevalent rather than incident cases in earlier years, changes in disease understanding and diagnostic criteria, and changing demographics over time. Future registers are at risk of funding shortfalls and changes to privacy legislation. Notwithstanding, as heterogeneities of clinical phenotype and disease pathogenesis are increasingly recognized in the neurodegenerations, well-designed longitudinal population-based disease registers will be an essential requirement to complete clinical understanding of neurodegenerative diseases.

Age-period-cohort analysis of trends in amyotrophic lateral sclerosis incidence

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease with an unknown cause. Studies have reported that the incidence rate of ALS might be changing. As ALS is an age related disease, crude incidence could increase as population structure changes and overall life expectancy improves. Age-period-cohort (APC) models are frequently used to investigate trends in demographic rates such as incidence. Age-specific incidence rate for ALS from 1996 to 2014 were taken from a population-based ALS register in Ireland. To circumvent the well-known identifiability issue in APC models, we apply the method of Partial Least Squares Regression to separate the effects of Age, Period and Cohort on ALS incidence over time. This APC analysis shows no cohort effect and the initial signs of a period effect; increasing incidence of ALS in the most recently diagnosed group. As further years of data accrue to the Irish register it will become clear if this effect emerges as a strong trend in the incidence of ALS in Ireland and replication of these analyses in other populations will show if our findings on temporal patterns in ALS incidence are shared elsewhere.