## 2 Examples of Cohort Studies and Integration of Cohorts  
Cohort studies allow for one to answer different epidemiological questions regarding the association between an exposure factor and a disease, such as whether exposure to smoking is associated with the manifestation of lung cancer. The British Doctors Study, which started in 1951 (and continued until 2001), was a cohort study that comprised both smokers (the exposed group) and non-smokers (the unexposed group) [18]. The study delivered substantial evidence of the association of smoking with the prevalence of lung cancer by 1956. In a cohort study, the groups are selected in terms of many other variables (i.e., general health and economic status), such that the effect of the variable being evaluated, i.e., smoking (independent variable), is the only one that could be associated with lung cancer (dependent variable). In this study, a statistically significant increase in the prevalence of lung cancer in the smoking group when compared to the non-smoking group rejects the null hypothesis of the absence of a relationship between risk factor and outcome. Another example is the Avon Longitudinal Study of Parents and Children (ALSPAC), a prospective observational study that examines the impacts on health and development across the life course [19]. ALSPAC is renowned for investigating how genetic and environmental factors affect health and growth in parents and children [20]. This study has examined multiple biological, (epi) genetic, psychological, social, and environmental factors that are associated with a series of health, social, and developmental outcomes. Enrollment sought to register pregnant women in the Bristol area in the UK during 1990-92. This was prolonged to comprise additional children that are eligible up to the age of 18 years. In 1990-92, the children from 14,541 pregnancies were enrolled, which increased the number of participants enrolled to include 15,247 pregnancies by the age of 18 years. The follow-up comprised 59 questionnaires (four weeks-18 years of age) and nine clinical assessment visits (7-17 years of age) [19]. Genetic (the DNA of 11,343 children, genome-wide data for 8365 children, complete genome sequencing for 2000 children) and epigenetic (methylation sampling of 1000 children) data were collected during this study [19]. The federated model is more often used in multi-center studies, large national biobanks, such as the UK Biobank [21], and meta-analyses projects combining data from different registries or databases. It requires new methods and systems to handle large data collection and storing. One example is the Cross Study funded by the National Institutes of Health (NIH). In this project, data are combined from three current longitudinal studies of adolescent development with a specific emphasis on recognizing evolving pathways that are prominent in substance use and disorder [22]. All three studies oversampled offspring who had at least one biological parent affected by alcohol use disorder and comprised a matched sample of healthy control offspring of unaffected parents. The Michigan Longitudinal Study [23] is the first study that has collected a comprehensive dataset in a large sample of 2-5 year olds subjects who were evaluated via four waves of surveys up to early adulthood. The Adolescent and Family Developmental Project [24] is the second study that recruited families of adolescents aged 11-15, with the surveys being distributed well into adulthood. The Alcohol, Health, and Behavior Project [25] is the third study to include intensive assessments of college freshmen, who, up to their thirties, participated in more than six waves of surveys. Collectively, these three studies span the first four decades of life, mapping the phases when early risk factors for later substance outcomes first emerge (childhood), substance use initiation typically occurs (adolescence), top rates of substance use disorders are evident (young adulthood), and deceleration in substance involvement is evident (adullhood).