Development of the global inflammatory bowel disease visualization of epidemiology studies in the 21^st century (GIVES-21)

Inflammatory bowel diseases (IBD) are chronic illnesses with significant morbidities and impact on patients’ quality of life due to an unpredictable relapsing and remitting course, development of complications, requirement of hospitalisations, surgeries, and use of costly therapies. It is estimated that more than 7 million people in Europe and the United States will be suffering from IBD by 2030 [1], and its prevalence is estimated to be more than 0.3% in North America, Oceania, and many countries in Europe by 2030 [2‐4].

In the 21st century, newly industrialized countries in Asia and Latin America are witnessing a rapidly rising incidence mirroring the epidemiology of Crohn’s disease (CD) seen in the Western world in the latter half of the twentieth century [2, 5, 6]. In contrast, countries in the West are experiencing compounding disease prevalence whereby incidence has stabilized but prevalence is forecasted to reach at least 0.5% of the population in the next decade due to IBD incidence rates being in excess of IBD mortality [7, 8]. This rise in the prevalence of IBD will lead to a substantial increase in the burden of health care systems and society. Mitigating the global burden of IBD will require a concerted effort of disease prevention and healthcare innovations that respond to the changing demographics of IBD population across the world [9].

To date, most epidemiological studies have originated from high income countries and countries in the West whereas there are a lack of prospective, population-based, incidence data from developing countries with lower socioeconomic status [10], including Eastern and Southern Asia, the Middle East, Africa and Latin America [2, 5]. It is of paramount importance to understand the epidemiology of IBD in these regions where data remained scanty in order to quantify the magnitude of the problem globally, to appreciate the public health burden of IBD and to allow appropriate allocation of resources. Defining epidemiology and environmental exposure in IBD in developing and newly industrialized countries can also potentially provide researchers with clues to disease aetiology contributing to the rapid increase of IBD in these regions. In this paper, we report the methodology adopted to study the incidence of IBD in newly industrialized countries and developing countries and to evaluate the impact of dietary factors on IBD development.

To the best of our knowledge, this is one of the most diverse and comprehensive epidemiology platform covering more than 20 countries in Asia, Latin America and Africa studying the epidemiology of IBD and environmental and dietary factors associated with development of IBD with a focus in newly industrialized and developing regions. The success of this initiative relied on the development of a global network of gastroenterologists, surgeons and primary care physicians who have clinical and/or epidemiological interest in IBD. This global network served as custodians to ensure the accuracy of the data presented on our online atlas. Custodians from regions that currently lacked population-based data had taken on leading role in conducting ground-level epidemiological research to establish the burden of IBD in their respective countries within GIVES-21. The unique outcome of the GIVES-21 consortium would include an updated incidence of IBD in knowledge-gap areas, understanding the geographical effect on disease activity, differences in disease phenotype and understanding the association of food additives with the development of IBD in newly industrialized regions.

An ideal epidemiologic incidence study should be population-based, with uniform diagnostic criteria and strict case definitions, complete case ascertainment over a defined period time based on a stable and well-defined population. The low population incidence of IBD in many low- and middle-income countries made this challenging so we adopted an approach to include custodians who were capable to engage IBD specialists, pathologists, radiologists, endoscopists and colorectal surgeons within sentinel hospitals that diagnosed and followed-up IBD patients, using a standardized criteria and infrastructure. We recognize that any missed new IBD incident cases would contribute to under representation of incidence data. To overcome missing incident cases, initiation meetings were organized for all custodians and their respective networks of investigators including surgeons, gastroenterologists, pathologists and IBD nurses across public and private sectors to raise awareness and enhance the comprehensiveness of the enrolment of IBD incident cases. This also involved identifying patients that had yet to receive a formal IBD diagnosis (ie. Indeterminate cases or suspected cases) but had been treated with milder form of IBD medications during the study period. Medical records were screened by the custodians and investigators to exclude cases whose final diagnosis were of infectious causes. We anticipated that smaller and more stable catchment areas that were geographically contained with limited access to external IBD care would achieve close to 100% capture of all incident IBD cases. Most of the regions had a well-defined catchment area and an established network of IBD healthcare providers that included public secondary and tertiary hospitals with close network with primary care and would be able to capture at least 90% of the incident cases during the study period.

IBD is believed to be related to the activation of the intestinal mucosal immune system in response to dysbiosis of the gastrointestinal tract in genetically susceptible individuals [21, 22]. Various environmental risk factors have been implicated in the pathogenesis of IBD, one of which is diet [23]. Certain nutrients and food additives can impact on the gut microbiome and their interactions with the host may play a role in the pathogenesis of IBD [24, 25]. Consumption of ultra-processed food had increased over the last decade in industrialized countries, and epidemiological studies had found associations between ultra-processed food consumption and chronic diseases. Emerging preclinical evidence show that consumption of food additives was associated with gut dysbiosis and may contribute to the development of gut inflammation [26]. Two commonly used emulsifiers, carboxymethylcellulose and polysorbate-80 (P-80) in low concentration have been shown to induce low grade inflammation in gut and colitis in predisposed mice via alterations in the gut microbiome [27, 28], Further studies are now required to identify the potential culprit in ultra-processed food, such as a poor nutritional composition or the presence of food additives. While evidence of varying quality had identified potential harmful or beneficial dietary components, physicians and patients currently do not have guidance as to which foods are safe, may be protective or deleterious for their apart from a recent guidance document compiled by the nutrition cluster of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) [29]. We have included the food additive questionnaires to capture these data in a diverse population that hoped to shed insight into diet impact on different IBD populations.

Performing questionnaire study across different regions and populations might have inherent issues due to cultural and dietary differences. To limit this bias, we have invited regional custodians and dietitians to review all questionnaires to accommodate the diversity of environmental and dietary factors and availability of processed food in each respective region. Like all questionnaire studies, missing data and recall bias especially on questions regarding early life factors and dietary intake are inevitable. The inception nature of this study lowers the rate of recall bias when compared with hospital-based or retrospective cohort, although any recall bias is unavoidable in questionnaire-based study. We believe that some factors may be less affected by recall bias, such as breast feeding, current food additives intake. Validation of questionnaires generally require forward and backward translation which was not formally performed in this study. However, to overcome the potential pitfalls without forward and backward translation, we have employed professional translation service to translate them into local languages and each regional custodian were actively involved in reviewing each question to ensure the languages are adaptable and understandable by their respective population before disseminating them to our study participants.

Unlike Nordic countries that have healthcare insurance code and nationwide registry to capture IBD cases, no such systems exist in most areas in the world whereby IBD data are lacking. One of the major challenges in conducting incidence study where by insurance of also include potential difficulties such as identifying all incident IBD cases in the catchment areas, especially in areas where technology or internet coverage is less developed. Regions that had a mobile population or a disjointed healthcare network with a diverse range of IBD care providers may face difficulties to capture all IBD incident cases. We anticipate that a small proportion of centers would only be able to provide hospital-based data on incidence which would lead to an underestimation of new cases. Nonetheless, there is a current knowledge gap on the epidemiology and outcomes of patients with IBD in these newly industrialized regions. Any hospital-based data would still be valuable. Another potential challenges would be the continuation of follow-up for newly recruited patients with IBD, especially during the current COVID-19 pandemic. We anticipated that least 80% of the newly recruited incident IBD cases will complete 6-month follow up and 50% will complete a 12-month follow up by June 2023.

In conclusion, the burden of IBD is rising globally, with substantial variation in levels and trends of disease in different countries and regions. Understanding these geographical differences is crucial for formulating effective strategies for preventing and treating IBD. We believe new data arising from the GIVES-21 consortium will provide essential data to knowledge users, healthcare providers, policy makers who can prepare their healthcare systems for the rising global burden of CD and UC.