Workpackage 7: Exposome




To establish the quantitative exposome in population-based cohorts


To provide biological material associated with well characertized exoposome profiles that can be integrated to higher level system analysis


Task 1. Collection and analysis of exposome data (partners 1, 8, 10, 11). Exposomics data will be collected in the countries involved in Euro-MOTOR and EURALS running population-based ALS registries (Ireland, Italy, The Netherlands). In each country, a dedicated research associate will be responsible for case finding, identification of matched controls, enrolment and monitoring. Training and validation of questionnaire will take place within the first six months, using methodologies already established by the EURALS group (Beghi et al, 2009).

Euro-MOTOR will collect data from one population-based discovery cohort (400 patients and 400 controls) and one population-based replication cohort (400 patients and 400 controls), to be used throughout all workpackages. Only for the Exposome WP questionaires will be further collected for at least 1600 patients and 3200 controls in total.

For each patient two age (+/- 2.5 years) and sex-matched population-based controls will be identified through random selection using family practitioner lists.

A previously validated questionnaire currently in operation by the EURALS group (Beghi et al, 2009) will be modified in the context of a Job and Task Exposure Matrix (JEM, TEM)  (Kauppinen et al, 1998).  Cases and controls will be interviewed by telephone at home. Controls will be interviewed by appointment in the GP’s office home or at home.

The following definitions will be used for risk factors and exposures:

Physical exercise is defined as having spent time engaged in physical activities relating to work, sport, or both. Physical activity is defined by the degree of energy consumption and is calculated using the so called “Metabolic Equivalent” (MET), which is the ratio between the metabolic rate caused by a given activity and the standardized metabolic rate at rest (1kcal/kg/hour) (Ainsworth et al, 1993 and 2000).

Organized sport activity: any sport practiced for at least one year, documented by joining a given sport association and by participation to official competitions; where possible, sport activities will be categorized by type and duration;

  1. Trauma: any traumatic event occurring during sport/leisure or work activities and requiring hospitalization and/or temporary or permanent disability; where possible, each trauma will be categorized by type and duration;
  2. Drugs taken during sport activities: any pharmaceutical compound taken for a cumulative period of at least one month to improve performance or to treat sport-related traumas; where possible, each drug will be categorized by type and duration of exposure.
  3. Exposures to chemical, pesticides and electromagnetic fields in the course of work, or when engaged in leisure activity. Where possible, each exposure will be categorized by type, duration of exposure, and context (occupational / recreational)

Task 2. Apply Job Exposure Matrices (partners 1, 8, 10)

Occupations will be coded according to the International Standard Classification of Occupations (ISCO-88).  The ISCO-88 coding scheme allows for a classification after subjects have provided their own answers regarding their occupational history. The JEMs that are available to Euro-MOTOR are for electromagnetic field exposures (EMF), pesticides (e.g. insecticides/herbicides), solvents (e.g. aromatic hydrocarbons), inhaled compounds (e.g. dusts, gases, vapours and fumes) and physical activity. (Ainsworth et al, 1993 and 2000; Sutedja et al, 2009)

The subjects are requested to list their successive job episodes, with the period (start and end dates), employer’s name, activity sector, and job, all as free response questions. Each questionnaire is then coded manually by specially trained staff, following the international classifications of occupations (ISCO). This coding scheme allows for a quantitative, individual exposure assessment for all cases and controls.

Depending on the nature of the JEM, data will be analyses as continuous of categorical levels, using multivariate logistic regression, adjusting for country, smoking, socio-economic status, gender and age. Cox regression analyses will be used to assess associations with disease progression/survival status of the cohort.

Data Collection

For each patient and control the phenotype will be defined by recording the following demographic and clinical variables in an ad-hoc semi structured questionnaire: age, sex, race, marital status, height, weight, body mass index (BMI), cognitive status (using standardized screening tools) and family history of Alzheimer’s disease (AD) Parkinson’s disease (PD) and other neurodegenerative conditions. In addition, each patient and matched control will be interviewed using a standardized validated questionnaire constructed in the context of a pre-determined Job Exposure and Task Exposure Matrix. 

Details will include the following:

1. Occupation (Type, grade, duration, likely exposures to risks of physical activity, chemical, pesticides, toxins and electromagnetic fields) 

2. Physical exercise: Each work- and sport-related physical activity will be detailed and coded separately, and METs accordingly calculated. Sport activities will be also coded as amateur, organized and professional.

3. Trauma will be coded with respect to the number of events, severity, complications (hospitalization, transient or permanent disability), and site of injury (head, arms, chest, abdomen and legs).

4.  Drugs taken for at least one month during sport activities or to treat sport-related complications will be recorded, with type, year of start and year of cessation.

5.  Exposure to chemicals, organic pesticides and electromagnetic radiation will be identified and recorded in occupational and recreational settings. Alcohol and tobacco history will be also collected.

In addition, in patients with ALS the following information will be required: El Escorial diagnostic category, site of onset, disease duration at entry.

Parametric and non-parametric tests will be used after verification of the distribution of each variable’s values. The Student’s t test (or the Wilcoxon test when a non-parametric equivalent is required) will be used to test height, weight, BMI, MET, duration of occupation, duration of physical exercise, number of traumatic events, disease duration (only cases), duration of drug and toxin exposure. The chi-square test will be used to test all categorical variables: center, demographics, El Escorial diagnostic category (only cases), site of onset (only cases). A Job Exposure Matrix will be conducted with respect to occupation, trauma, drugs (individual and by category), toxins, pesticide, heavy metals alcohol and tobacco exposure (yes/no).

The ORs and 95% CI will be calculated using univariate and multivariate (logistic regression analysis) models,

Sample size

Based on the size of the population at risk (36 million), a conservative estimate of the patients with ALS to be recruited is 820 per year (or 2 per 100,000 per year). This number reflects the possibility that less than 75% of patients will give their informed consent. This will yield ~1600 cases and ~3200 controls with environmental data over the 3-year study period.

Given the sample size required by the protocol (1600 cases and 3200 controls), the study is 80% powered to detect a 1.2% difference (Odds Ratio 2.05) with a 1% level of exposure in the controls and a 2.46% level of exposure in the cases. With an OR>3, statistical significance will be automatically obtained for all levels of exposure greater than 1%.