The French E3N Prospective Cohort Study (E3N)

The French E3N Prospective Cohort Study (Etude Epidémiologique auprès de Femmes de la Mutuelle Générale de l'Education Nationale)

The French E3N cohort was initiated in 1990 to investigate the risk factors associated with cancer and other major non-communicable diseases in women.

The participants were insured through a national health system that primarily covered teachers, and were enrolled from 1990 after returning baseline self-administered questionnaires and providing informed consent. The cohort comprised nearly 100 000 women with baseline ages ranging from 40 to 65 years.

Follow-up questionnaires were sent approximately every 2-3 years after the baseline and addressed general and lifestyle characteristics together with medical events (cancer, cardiovascular diseases, diabetes, depression, fractures and asthma, among others). The follow-up questionnaire response rate remained stable at approximately 80%.

A biological material bank was generated and included blood samples collected from 25 000 women and saliva samples from an additional 47 000 women.

Ageing among the E3N cohort provided the opportunity to investigate factors related to agerelated diseases and conditions as well as disease survival.

Study Overview

• Status: Active, not recruiting
• Conditions: Depression; Cardiovascular Diseases; Melanoma; Hypertension; Diabetes; Breast Cancer; Parkinson Disease; Inflammatory Bowel Diseases; Asthma; Endometriosis; Crohn Disease; Endometrial Cancer; Colo-rectal Cancer; Thyroid Cancer

Detailed Description

Who is in the cohort? In June 1990, a questionnaire was sent to 500 000 women who had been born between 1925 and 1950 and were insured by the Mutuelle Générale de l'Education Nationale (MGEN), a national health insurance plan that primarily covers teachers. The questionnaire was sent along with a leaflet explaining that an Inserm research team was launching a study of cancer risk factors and that participation would require filling in questionnaires every 2-3 years as well as the submission of a signed consent form providing permission to obtain information about each participant's vital status, address changes and medical expense reimbursements from the insurance plan. Nearly 100 000 women volunteered.

How often have they been followed-up? Until now, nine follow-up questionnaires have been sent every 2-3 years from the baseline. Approximately half of the answers were obtained after the first mailing. Two reminders were sent thereafter. The questionnaires were accompanied with newsletters that informed participants about the major results obtained to date. The participation rate remained high (77-92% according to the questionnaires) and the lost to follow-up rate was minimal because of the ability to trace non-respondents through their insurance plan files. The questionnaires were accurately filled in, with few missing or unacceptable answers.

What has been measured? To date, 11 self-administered questionnaires have been sent. The collected data are sociodemographic factors, anthropometric measurements, reproductive factors, hormonal treatments, health behaviour and lifestyle. Each follow-up questionnaire also recorded the participant's health status. The questionnaires are available at www.e3n.fr .

The questionnaires are anonymous and identified with an identification number and pin code that can be rapidly scanned to identify the respondents. The questionnaires are optically scanned and all answers are checked on screen. The scanned images are saved to allow data entry at a later time, including information regarding the addresses of medical doctors (18 000 to date) or drug names (pre-listed to avoid errors). The longitudinal data (repeats of identical questions for the purpose of updating information about topics such as menopause or smoking) are routinely homogenized. Several validation studies (e.g. dietary and anthropometrical data studies) have been performed and have revealed very satisfactory results.

Self-reported cases of cancer are validated and coded after reviewing the pathology reports obtained from medical practitioners, and nearly 90% of all cancer cases are histologically confirmed. Other diseases are also validated (e.g. diabetes, myocardial infarction, stroke, Parkinson disease) by requesting additional information about the participants (e.g. glycosylated haemoglobin levels, fracture-related circumstances, drug names) and sending questionnaires to medical doctors.

Additionally, a biological material bank was generated. Blood samples were initially collected from 1994-99. The participation rate among the invited participants was approximately 40%; this yielded approximately 25 000 blood samples that were each separated into 28 aliquots (e.g. plasma, serum, leukocytes, erythrocytes). Plastic straws were used to store each participant's samples in liquid nitrogen containers. The bio-repositories are located at the IARC (Lyon) and the EFS (Etablissement Français du Sang, Annemasse). Since 2004, approximately 10 case-control studies have been conducted (approximately 1 800 cases and 3 500 controls) with regard to the measurements of various biomarkers (e.g. fatty acids, calcium, vitamin D, vitamin B, cholesterol and C-reactive protein). A metabolomics study is currently ongoing.

From 2009-11, saliva samples (Oragene, DNA Genotek, Kanata, ON, Canada) were requested from 68 242 living women and were obtained from 47 000 women (participation rate, 69%). Salivary DNA has been extracted and has been used for genotyping in two case-control studies (approximately 2 500 cases and 850 controls) since December 2010.

The research team is currently planning to set up a tumour tissue bank and will begin with the collection of breast cancer tissues.

What has it found? The E3N cohort has produced a spectrum of results regarding the complex roles played by nutrition, hormonal factors, physical activity, anthropometric characteristics and other major lifestyle-related factors with respect to various diseases.

• Study Type: Observational
• Enrollment (Actual): 100000

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 36 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

• Sampling Method: Probability Sample

Study Population

The cohort comprised nearly 100 000 women with baseline ages ranging from 40 to 65 years, all insured through a French national health system (MGEN).

Description

Inclusion Criteria:

• only women
• born between 1925 and 1950
• insured by the Mutuelle Générale de l'Education Nationale (MGEN)

Exclusion Criteria:

- men

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Anthropometric measurements	Height, weight, hip circumference and waist circumference	From 1990 until now
Educational level		1990
Professional activity	Insee categories	1992 and 2005
Age at cessation of activity		From 2005 until now
Menstrual factors	Age at menarche, length of menstrual cycle	From 1990 to 2002
Reproductive history	Number of pregnancies, age at each pregnancy, durations and outcomes of pregnancies, breastfeeding, infertility	From 1990 to 1992
Menopause	Age, type	1990, 1995, 1997, 2000, 2002, 2005
Hormonal Treatments	Menopausal Hormonal Treatments (MHT), oral contraceptives	From 1992 to 2008
Tobacco consumption	Type, quantity, time of smoking	From 1990 until now
Alcohol consumption	Type of alcohol, quantity	1993, 1997, 2005
Physical activity	Moderate and intense activity, sedentarity	1990,1997,2002, 2005, 2014
Diet questionnaire	Precise annual diet questionnaire	1993 and 2002
Family history of diseases	Cancer, diabetes and cardiovascular diseases	1990 to 2005
Medication use	linked with the drug reimbursement files from the health insurance	From 1990 until now
Medical and surgical history		From 1990 until now
Mental Health	Centre for Epidemiologic Studies Depression Scale (CESD) and Depression	From 1990 until now
Health outcomes		From 1990 until now

Collaborators and Investigators

• Sponsor: Institut National de la Santé Et de la Recherche Médicale, France
• Collaborators: Gustave Roussy, Cancer Campus, Grand Paris; Ligue contre le cancer, France; Université Paris-Sud
• Investigators: Study Director: Gianluca Severi, PhD, INSERM (Institut National de la Sante et de la Recherche Medicale); Principal Investigator: Marie-Christine Boutron-Ruault, PhD, INSERM (Institut National de la Sante et de la Recherche Medicale)

Publications and helpful links

General Publications

• Clavel-Chapelon F; E3N Study Group. Cohort Profile: The French E3N Cohort Study. Int J Epidemiol. 2015 Jun;44(3):801-9. doi: 10.1093/ije/dyu184. Epub 2014 Sep 10.
• Frenoy P, Perduca V, Cano-Sancho G, Antignac JP, Severi G, Mancini FR. Application of two statistical approaches (Bayesian Kernel Machine Regression and Principal Component Regression) to assess breast cancer risk in association to exposure to mixtures of brominated flame retardants and per- and polyfluorinated alkylated substances in the E3N cohort. Environ Health. 2022 Feb 26;21(1):27. doi: 10.1186/s12940-022-00840-4.
• Madika AL, MacDonald CJ, Gelot A, Hitier S, Mounier-Vehier C, Beraud G, Kvaskoff M, Boutron-Ruault MC, Bonnet F. Hysterectomy, non-malignant gynecological diseases, and the risk of incident hypertension: The E3N prospective cohort. Maturitas. 2021 Aug;150:22-29. doi: 10.1016/j.maturitas.2021.06.001. Epub 2021 Jun 12.
• Laouali N, Shah S, MacDonald CJ, Mahamat-Saleh Y, El Fatouhi D, Mancini F, Fagherazzi G, Boutron-Ruault MC. BMI in the Associations of Plant-Based Diets with Type 2 Diabetes and Hypertension Risks in Women: The E3N Prospective Cohort Study. J Nutr. 2021 Sep 4;151(9):2731-2740. doi: 10.1093/jn/nxab158.
• Cairat M, Al Rahmoun M, Gunter MJ, Severi G, Dossus L, Fournier A. Antiplatelet Drug Use and Breast Cancer Risk in a Prospective Cohort of Postmenopausal Women. Cancer Epidemiol Biomarkers Prev. 2021 Apr;30(4):643-652. doi: 10.1158/1055-9965.EPI-20-1292. Epub 2021 Feb 2.
• Azevedo Da Silva M, Fournier A, Boutron-Ruault MC, Balkau B, Bonnet F, Nabi H, Fagherazzi G. Increased risk of type 2 diabetes in antidepressant users: evidence from a 6-year longitudinal study in the E3N cohort. Diabet Med. 2020 Nov;37(11):1866-1873. doi: 10.1111/dme.14345. Epub 2020 Jul 2.
• Mahamat-Saleh Y, Cervenka I, Al Rahmoun M, Savoye I, Mancini FR, Trichopoulou A, Boutron-Ruault MC, Kvaskoff M. Mediterranean dietary pattern and skin cancer risk: A prospective cohort study in French women. Am J Clin Nutr. 2019 Oct 1;110(4):993-1002. doi: 10.1093/ajcn/nqz173.

Helpful Links

• website of the study

Study record dates

Study Major Dates

• Study Start (Actual): June 15, 1990
• Primary Completion (Actual): November 15, 1991
• Study Completion (Anticipated): December 15, 2025

Study Registration Dates

• First Submitted: July 27, 2017
• First Submitted That Met QC Criteria: September 12, 2017
• First Posted (Actual): September 15, 2017

Study Record Updates

• Last Update Posted (Actual): September 19, 2017
• Last Update Submitted That Met QC Criteria: September 18, 2017
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Uterine Neoplasms; Genital Neoplasms, Female; Uterine Diseases; Gastrointestinal Diseases; Gastroenteritis; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Intestinal Diseases; Cardiovascular Diseases; Parkinson Disease; Inflammatory Bowel Diseases; Endometriosis; Crohn Disease; Endometrial Neoplasms
• Other Study ID Numbers: C 95-01