Studying inflammatory bowel disease etiology: a life course approach
Background and importance. IBD is a group of chronic relapsing inflammatory disorders of the gastrointestinal tract. Only few risk or predictive factors have been strongly established for CD and UC, including family history, cigarette smoking, and appendectomy. Identifying risk factors was recently rated as the top priority in pediatric and adolescent IBD research by Canadian patients, caregivers, and health professionals. It has been hypothesized that exposures during critical time windows may interfere with the gut microbiota and lead to an increased risk of IBD. Yet, there has never been a formal assessment of possible etiological pathways considering the long term effect of early life exposures, the temporal ordering of various exposures, and disentangling the direct effects from those that occur through intermediary factors.
Research aims. This project’s overarching goal is to identify life periods in which medical, lifestyle, and psychosocial factors have the highest impact on the risk of developing CD and UC, respectively, and determine which factors are most promising for prevention programs. Applying a life course approach, we will explicitly assess the importance of duration and timing of exposures, formally study the inter-relations between these factors and disease risk, and estimate the burden of disease attributable to these factors.
Methods and expertise. This project builds on the Quebec Birth Cohort on Immunity and Health. Established through linkage of provincial administrative databases, this cohort includes 400,611 individuals born from 1970 to 1974 in the Province of Quebec. Data on medical services and hospitalizations for IBD were obtained until 2014. A total of 4100 IBD cases was identified by applying a validated definition based on use of health services. Using a nested case-control design, we will recruit 2600 randomly selected participants (1000 controls, 1000 individuals with CD, and 600 with UC). Information will be gathered through a web survey. A life grid technique will be integrated to minimize recall bias and enhance memory. Factors of interest will be documented along the life course. They include birth circumstances, breastfeeding, antibiotic use, oral contraceptive use, appendectomy, smoking, diet, and psychosocial factors (anxiety, depression, stress). Family history of IBD, sociodemographic characteristics and socioeconomic position will also be documented. Statistical analyses will be conducted separately for CD and UC, and will be based on a structured modeling approach using a series of unconditional logistic regressions to test which life course etiological models best fit the data. Mediation and interactions will be assessed. Finally, we will estimate the attributable fraction due to a given exposure over several life periods and to several exposures in a given life period. We have assembled a unique team, combining expertise in epidemiology, biostatistics, life course approach, perinatal exposures, and gastroenterology.
Expected outcomes. Our distinctive contribution will be to formally consider the timing of exposures and the relations between different types of exposures by applying a life course approach. We will estimate the public health impact of these factors to inform policy. In line with the objectives of the Project Grant program, this study will generate new knowledge on the complex etiology of this highly debilitating disease, which represents a crucial step towards prevention.
Collaborators: Prévost Jantchou, Andrea Benedetti, Sylvie Girard, Sreenath Madathil, Belinda Nicolau, Shu Qin Wei
Bacillus Calmette-Guerin (BCG) vaccination and multiple sclerosis: a population-based study in Quebec
Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system. MS is the leading cause of non-traumatic disability among young adults, and thus has important individual and societal impacts. The causes of MS are not known, but some environmental factors have been associated with disease risk such as place of birth, sex, race, smoking, Epstein Barr Virus (EBV) exposure, and vitamin D exposure through sun and diet. It is generally recognized that the immune system is directly involved in the pathophysiology of MS. In this sense, factors having an impact on the immune system are good candidates to investigate in relation to MS etiology, as either beneficial or harmful agents.
In this project, we focus on the Bacillus Calmette-Guerin (BCG) vaccine and its potential immunomodulatory role on MS development. Only six epidemiological studies to date have addressed BCG vaccination and the risk of developing MS. A meta-analysis on immunizations and MS, suggested a lack of association between BCG vaccination and MS, but these studies presented limitations such as limited sample size, use of questionnaire data to define BCG status, and extreme proportions of vaccination (very low or very high). Considering these limitations, there is a need for a methodologically sound and well-powered study on early life BCG vaccination and risk of MS. Quebec is a uniquely appropriate setting for such a study, since a province-wide BCG vaccination program was held between 1949 and 1974, and vaccination information was compiled in a registry.
Our main objective is to determine whether BCG vaccination is associated with the risk of multiple sclerosis. As a secondary objective, we will assess the impact of age at BCG vaccination with a particular interest in vaccination during the first year of life.
We will expand an existing population-based cohort, the Quebec Birth Cohort on Immunity and Health (QBCIH), originally designed to assess non-specific effects of BCG vaccination on inflammatory and autoimmune diseases. Established through probabilistic record linkage of provincial birth, death, and BCG vaccination registries, as well as administrative databases, the QBCIH includes 81,496 persons, representing 90.5% of those born in Quebec in 1974 at or after 32 weeks of gestation. For this project on MS, we will substantially augment the study population size and duration of follow-up. We will assemble a large retrospective cohort of individuals born from 1970 to 1974, in which the QBCIH will be included. Data will be gathered from administrative databases until 2013, and will include sociodemographic and perinatal factors, information on death if applicable, BCG vaccination, as well as data on medical services and hospitalizations for MS. A validated definition based on use of health services will be applied to identify MS cases.
This project constitutes a creative approach to studying MS etiology, a crucial aspect for prevention given the few known modifiable causal factors. By studying an existing vaccine which could contribute to MS prevention through a non-specific effect, this project can have tangible repercussions in MS prevention.
Collaborators: Andrea Benedetti, Christina Wolfson, Pierre Duquette, Nathalie Arbour
Funding: Multiple Sclerosis Society Of Canada (MSSOC), CIHR
Impact of Bacillus Calmette-Guerin (BCG) vaccination on the risk of lymphoma
BCG vaccination was used in Quebec until 1974 to prevent tuberculosis. The goal of Dr. Marie-Claude Rousseau’s research is to understand other effects that BCG vaccination could have on various diseases. In this project, our team will evaluate if having received the BCG vaccine as a child could prevent lymphoma later in life, as it was suggested by a study conducted in Denmark. We have recently created a cohort of 81,496 persons born in Quebec in 1974 by linking several sociodemographic and medical databases. We will obtain information on medical visits and hospitalizations related to lymphoma until 2013. We will then compare the occurrence of lymphoma among persons who received the BCG vaccine and those who did not. Only a few epidemiological studies were conducted to investigate the effect of BCG vaccination on the risk of developing lymphoma. These studies had methodological problems that do not allow concluding on this question. Some were too small, and others had many participants who left the project before the study was over. In most studies, information about BCG vaccination was reported by the participants instead of coming from health records, which is usually more accurate. Age at vaccination was never considered, but it should be. The effect of BCG on lymphoma could be different if the vaccine was given very early or later in life. A recent study, well designed but small, suggested that persons who received the BCG vaccine were 50% less likely to develop lymphoma than those who were not vaccinated. In this context, we hypothesize that the BCG vaccine has a protective effect on lymphoma. We designed a study which will allow us to test this hypothesis. The BCG vaccine stimulates some cells from the immune system which may help prevent lymphoma. Our team wants to assess if BCG vaccination is related to the risk of developing lymphoma. The effect of BCG vaccination will also be studied separately among persons who were vaccinated at 0-1 year old or later. We created a cohort of 81,496 persons born in Quebec in 1974 by linking provincial birth, death, and BCG vaccination registries, and databases from the healthcare system. We will use this cohort, called the Quebec Birth Cohort on Immunity and Health, for our project. Information related to lymphoma will be obtained from health databases until December 31 2013, when the subjects were 39 years old. This will include physician billing data for medical visits or hospitalizations. From the Quebec Tumor Registry, we will extract information on diagnosis of lymphoma and other cancers. We will compare the risk of developing lymphoma among those who were vaccinated and those who were not. In this project, we are studying a new factor in relation to the development of lymphoma. By studying an existing vaccine which could contribute to lymphoma prevention, this project can have a real impact on cancer prevention. Given that there are few known causes of lymphoma that people can control, it is important to explore all avenues. The existing Quebec Birth Cohort on Immunity and Health offers a unique opportunity to conduct our project. It provides a solid foundation on which we can build. The study setting offers nearly perfect conditions for studying this novel hypothesis. This project has the potential to greatly impact our understanding of the causes of lymphoma. It can lead to concrete preventive approaches to fight this cancer.
Collaborators: Andrea Benedetti, Marie-Élise Parent
Funding: Candian Cancer Society Research Institute (CCSRI)
Non-specific stimulation of the immune function in early age, Bacillus Calmette-Guérin (BCG)
I am currently conducting studies looking into a possible link between non-specific stimulation of the immune function in early age, such as that induced by Bacillus Calmette-Guérin (BCG) vaccination, and beneficial or detrimental effects on the development of inflammatory and autoimmune diseases later in life. For these studies, we are using information from the Quebec BCG vaccination registry and linking it to administrative health databases in order to determine occurrence of the diseases of interest. After completing a validation study, we assembled the Québec Birth Cohort on Immunity and Health (QBCIH, n=81,496) to study the association between BCG vaccination and childhood asthma. We are also studying BCG vaccination in relation to diabetes occurrence. Perinatal information, BCG vaccination and health encounters related to asthma, diabetes, and several allergic diseases were gathered from administrative databases. Additional relevant information, unavailable in these databases, was collected among 1643 participants using a two-stage sampling strategy with a balanced design. Analyses are ongoing for several sub-projects.
Collaborators: Andrea Benedetti, Mariam El-Zein, Richard Menzies, Marie-Élise Parent, Laurent Legault
Funding: FRQS, CIHR and ISQ
Quebec Research Program for Prostate Cancer Prevention
We initiated back in 2010, the Quebec Research Program for Prostate Cancer Prevention, which calls upon the collaboration of 12 established Quebec researchers covering environmental, occupational, infectious, lifecourse, molecular and genetic epidemiology, biostatistics and urology. This is probably the largest study ever to evaluate in such depth the possible environmental causes of prostate cancer. In brief, the Program has allowed us to build, on an existing research infrastructure, a major research effort including 12 objectives: (1) recruit 1,000 study subjects to bring the overall study sample of the Program to 4,000 subjects, (2) evaluate the presence of 110 chemicals in the subjects’ workplaces, (3) evaluate physical activity levels in workplaces, (4) evaluate dietary intakes, (5) collect information on all residences held by the subjects, (6) evaluate whether genetic factors determine how exposure to the environment relates to prostate cancer, (7) analyze hair and toenail samples as biomarkers of exposure to trace metals, (8) evaluate the determinants of prostate cancer progression, (9) create analytical databases, (10) conduct statistical analyses, (11) train students and research personnel, (12) disseminate findings. There are no doubts that with the wealth of information collected in the context of this Program, this collective effort in elucidating risk factors for prostate cancer will last for decades to come.
Collaborators: P. Karakiewicz, E. Franco, J. Siemiatycki, M. Goldberg, M-H. Roy-Gagnon, J. Lavoué, M. Abrahamowicz, A. Aprikian, F. Saad, A. Hsing, A. Chokkalingam, M-C. Rousseau, B. Nicolau
Funding: Société de recherche sur le cancer; Enseignment supérieur, Recherche, Science et Technologie de Québec; Fonds de recherche Santé Québec; RRSE; RioTintoAlcan; National Cancer Institute of Canada, Canada Research Society, MDEIE
For more information, including summaries of the main findings of this project, click here.
Development of an instrument for assessing occupational exposures in cancer case-control studies and its application to cancers of the lung, brain, ovary, and colon
Our research team has been active in studying occupational/environmental causes of cancer for over 30 years, having carried out several case-control studies and having developed and implemented a novel approach to assess past occupational exposures of subjects in case-control studies. Our method involved probing interviews followed by review of each work history by a team of industrial hygiene/chemistry experts to estimate the work exposures of each subject, using a checklist of 300 agents. In the course of our previous studies, our team of exposure experts, with over 50 person years of cumulated work devoted to the task, have assessed exposures in over 30,000 different jobs. The present proposal has two principal aims: (i) to make available to the international research community the benefits of a great deal of work we have done to link the jobs people have with the occupational agents they’ve been exposed to, in the form of a job-exposure matrix (JEM) and (ii) to apply the JEM to studies of lung, brain, ovarian and colorectal cancers. In addition, members of our team have assembled a geographic information system (GIS) called MEGAPHONE that includes extensive social and environmental information on Montreal neighbourhoods. MEGAPHONE can be applied to Montreal case-control subjects to estimate various neighbourhood environmental characteristics. CANJEM and MEGAPHONE will be applied to several case-control data sets as follows: 1) SYNERGY, an international consortium of lung cancer case-control studies, including over 29,000 subjects with lifetime occupational histories. The study currently involves estimation of exposures to 4 lung carcinogens by a team of experts. Our proposal is to use CANJEM to assign exposure to the other >200 agents in CANJEM and then analyse those associations. MEGAPHONE would only be applicable to the Montreal component of SYNERGY. b) The INTEROCC study is an international consortium of brain cancer case-control studies, in which job histories were collected on 9000 subjects. That project was designed to use a JEM developed in Finland. But FINJEM has limitations in its breadth of coverage and in its generalisability. Thus, we will implement CANJEM on the international brain cancer study. 3) An ovarian cancer case-control study is currently underway in our team focusing on inflammation and lack of vitamin D as risk factors. This study has also collected both residential and job histories from subjects. We intend to apply CANJEM and MEGAPHONE to this database to assess occupational/environmental risk factors for ovarian cancer. But because the study is currently underfunded to achieve adequate sample sizes for these variables, we will use some of the funding of this GRePEC project for 2.5 additional years of ovarian cancer data collection. 4) We have designed a case-control study to assess risk factors for colorectal cancer. Among the primary factors to be explored are those related to dental health and diet. But there will also be job and residential history acquisition and this will be used in conjunction with CANJEM and MEGAPHONE to assess occupational and environmental risk factors for colon cancer, including physical exertion at work. Collectively, these studies will produce a wealth of new data on occupational and environmental risk factors for four types of cancer.
Collaborators: Jack Siemiatycki, M. Abrahamowicz, B. Case, M. Daniel, G. Datta, E. Emami, M. Gérin, M. Goldberg, I. Karp, Y. Kestens, A. Koushik, F. Labrèche, J. Lavoué, M. Pollak, M. Van Tongeren
Funding: CIHR and Cancer Research Society, MDEIE, FRQS
Multi-centre international cohort study on the national history of oropharyngeal precursor lesions
I am involved in a multi-centre international cohort study on the national history of oropharyngeal precursor lesions. I lead the Canadian component at INRS-Institut Armand-Frappier, along with Dr. Belinda Nicolau (co-Principal Investigator) and a team of researchers from McGill University, Université de Montréal, and the Albert Einstein College of Medicine (NY, USA). This pilot project, conducted in Canada, USA, and Brazil will allow our group to implement and assess the procedures for an international prospective cohort study on oropharyngeal cancer precursors. In this study, we address molecular (gene expression, DNA methylation), infectious (human papillomavirus infections (HPV)), and lifestyle (smoking, alcohol, diet) factors associated with progression towards cancer. I am also investigating the role of HPV in Head & Neck cancer etiology as a co-investigator of the HeNCe Life study led by Dr. Nicolau. Moreover, I am co-leading an extension of this project in which we are detecting HPV in tumor samples in Canada and Brazil.
Collaborators: Belinda Nicolau, Paul Allison, Thomas Belbin, Martin J. Black, François Coutlée, Edouardo Franco, Michael P. Hier, Nicolas Schlecht
Funding: CIHR, MDEIE
Environmental causes of lung cancer
Finally, I am leading and participating to projects using data from a case-control study conducted by Jack Siemiatycki and collaborators in Montreal (1996-2002), and aiming to understand the environmental causes of lung cancer. Through student supervision and several collaborations, I am investigating several types of factors, from lifestyle to environmental exposures, in relation to lung cancer risk. For example, some of these projects covered dietary intake of carotenoids and vitamin C, body mass index, socioeconomic status, history of allergic diseases, as well as occupational exposures such as asbestos, formaldehyde, lead compounds, gasoline emissions, and cotton dust.
Collaborators: Michal Abrahamowicz, Bruce Case, Mark Goldberg, Igor Karp, Anita Koushik, Daniel Krewski, Jérôme Lavoué, Karen Leffondré
Funding: CIHR and Cancer Research Society, MDEIE, FRQS