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NorthPop

A research infrastructure under construction which includes a biobank and database for children and young adults in Västerbotten

NorthPop is a research infrastructure at Umeå University and Region Västerbotten under construction. It consists of a database and biobank containing extensive population-based, longitudinal data which are collected from 10 000 families or in total 30 000 children and young adults (the children's parents, who are 30 years of age on average).

Region Västerbotten and Umeå University have a successful tradition of research based on databases and biobanks, but existing infrastructures have previously almost entirely focused on middle-aged and older individuals, or specific diseases. There has previously been a complete lack of a population-based infrastructure with a biobank for children and young adults. There is however a great need for a database and biobank covering this young population as the majority of our lifestyle-related diseases and behaviors are established early in life. Children and young adults account for 50% of the population in Västerbotten (130 000 individuals). NorthPop, which predominantly covers the ages 0 to 30 years, therefore complements perfectly the Västerbotten Health Surveys (VHU), which cover the ages of 40 years and older, enabling completely new multi-generational research projects.

NorthPop is an open research infrastructure available to all researchers at Region Västerbotten and Umeå University, and also external researchers. Currently more than 30 PhD researchers are involved in the NorthPop project, at many different clinics of Region Västerbotten and departments of Umeå University. The researchers are already running over a dozen ambitious research projects based on the NorthPop infrastructure with questions on asthma/allergy, obesity, brain development, epigenetics, gut microbiota, environmental toxins, lifestyle/socioeconomics, mental health and digital media to name a few areas. The number of projects and researchers using the NorthPop infrastructure is expected to increase significantly over the coming years and the steering committee will work to ensure that the collected material with be used to its fullest for research. Data extraction will be decided by an Expert Group which will be appointed by the Registry and Biobank Consortium (RBKON), which is open to all researchers at Region Västerbotten and Umeå University.

We are convinced that NorthPop over the coming decades will develop into a very valuable research resource at Umeå University and for all of Västerbotten and contribute to world-leading cutting edge research.

Structure and data collection

All pregnant women in Västerbotten are invited to participate in NorthPop together with their partner and their child (current pregnancy). The children (and the whole family) are then followed longitudinally until the child is 7 years old. The parents give informed consent, which also includes access to data from other local and national databases such as the Healthcare medical records system, the National Board of Health and Welfare's diagnosis register, the Medical Register and the Statistics Sweden's LISA register. The infrastructure currently covers 60% of the population in Västerbotten (Umeå and Skellefteå) and will be expanded with a branch in Lycksele to cover all of Västerbotten.

The data collection includes questionnaires and biological samples (Fig 1). We use an advanced web-based survey system that sends out automated SMS and e-mails to the participants with a link to the questionnaires. During pregnancy, four part-questionnaires are answered by the mother and four by the partner. A series of part-questionnaires are then sent out when the child is 4 months, 9 months, 18 months, 2 years, 3 years and 7 years old. The response rate is up to 90% for most of the questionnaires.

Biological sampling includes blood samples from the pregnant woman in gestational week 28. The quality of these blood samples is very good. Blood samples from the child are taken from the umbilical cord at birth and we get samples from over 95% of the participants and these samples are of exceptionally good quality. Blood sampling at 18 months of age began in March 2018 and the next blood sampling, when the children are 7 years old, will start in 2023. All blood samples are centrifuged and then the following aliquots are saved: 10 plasma tubes, 2 tubes buffy coat and 10 tubes erythrocytes.

Other biological samples collected include a urine sample from the mother during pregnancy (week 18) as well as saliva and fecal samples from the children at 1, 4, 9 and 18 months and also at 3 and 7 years of age. In addition, a urine sample from the child and a breast milk sample from the mother are collected at 1 month of age.

Fig 1. Overview of the data collection in NorthPop

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Since the start in spring 2016, NorthPop has included over 9000 individuals (over 3000 families, data from November 2019). The goal is to include 10,000 families, i.e. 30,000 individuals, and this is expected to be achieved in 2023 according to current planning.

The database is located physically on servers at ICT Services at Umeå University and is located organizationally under Register Center North, Region Västerbotten. So far, it contains over 1 000 000 answers to questionnaire questions (data from November 2019).

The biobank containing NorthPop’s biological samples is stored in the Northern Sweden Biobank, Region Västerbotten. So far over 100 000 biological samples have been collected (aliquots of blood, urine samples, saliva samples, feces samples and breastmilk samples) (data from November 2019).

The amount of data in the database and the number of samples in the biobank will increase by factor 8 over the next six years.

Significance for research

Since NorthPop is a research infrastructure still under construction, we do not have as many users (affiliated researchers) as more established research infrastructures. We expect that the interest in the NorthPop infrastructure both among internal (Region Västerbotten/Umeå University) and external researchers will increase significantly over the coming years.

Currently, more than 30 PhD researchers at Region Västerbotten/Umeå University are involved in the NorthPop project. The researchers belong to Region Västerbotten clinics Pediatrics, Gynecology, Public Dental Service, Centre for Cancer, Rheumatology, Clinical Immunology, Dermatology and Child and adolescent Psychiatry. At Umeå University departments involved include Clinical Sciences, Odontology, Community medicine / rehabilitation, Radiation Sciences, Chemistry, Mathematical Statistics, Psychology, Sociology and Computing Science.

The affiliated researchers are already running over a dozen ambitious research projects based on the NorthPop infrastructure with research questions focusing on areas such as asthma/allergy, obesity, brain development, behavioral- and school issues, gluten intolerance, genetics, epigenetics, exposure to environmental toxins, lifestyle factors, socioeconomic factors, gut and oral microbiota, digital media and social support for parents, as well as stress and mental health during pregnancy.

The number of affiliated researchers is continuously increasing. We were, for example, contacted by Katharina Wulff, then a physiologist at Oxford University, who now has moved to Umeå and will partly be working with NorthPop data. Apart from the faculties already involved we also see great opportunity and potential for research in areas of pedagogy and language for example.

Most of the affiliated researchers have used (or plan to use) NorthPop in their applications for research funds, such as the Swedish Research Council, Forte and Wallenberg, Central ALF, Erling Persson's foundation, Heart Lung Foundation etc.

Social relevance

Most lifestyle-related diseases are difficult or impossible to cure so it would be very valuable to find effective preventative measures. Still, we know very little about the risk factors and mechanisms for the origin of these diseases. During the latest decades it has been more clearly shown that the fetus and the child’s early environment during pregnancy and the first two years of life (‘the first 1000 days’) are critical for the individual’s future health, far into adulthood. It concerns effects on growth, obesity, allergic diseases, neuropsychological functions, cardiovascular disease etc. Exposure during this sensitive period, through diet, environmental toxins, drugs, medications, infections, physical activity and other lifestyle factors have been suggested to exert programming effects on metabolism, immunity and induce epigenetic effects via methylations of specific genes, an effect that can be preserved during cell division and remain for the rest of life. Moreover, early exposure can probably affect the development of organ systems, such as the brain, lungs and cardiovascular system, and these effects could also be permanent. Most of our common lifestyle-related diseases and behaviors are established early in life but it is not known exactly which environmental factors are risk factors for the different diseases and the mechanisms are not yet fully known. The fetus lives in an almost completely sterile environment but is colonized quickly after birth by bacteria on the skin, in the mouth and in the gastrointestinal tract. The gut microbiota’s makeup has recently been connected to important diseases such as allergic disease, obesity and autoimmune diseases.

There is therefore a great need for a research infrastructure that gathers unique data related to exposures during pregnancy and the early childhood, genetic and epigenetic data as well as data on the development of the gastrointestinal microbiota so that these factors can be related to later health outcomes. A preventative measure early in life results in a much bigger effect on the lifelong health or the number of ‘functionally adjusted years of life’ than any measure taken later in life.

Young adults and children growing up today are exposed to completely different environmental factors than just 10 years ago. A sedentary lifestyle with a lot of screen-time and frequent use of smartphones and the internet comes with new health hazards, but also completely new opportunities to gather information in cohort studies. It is important to capture the new risk factors appearing in society and this means a need for new cohort studies with younger people who are exposed to these.  The risks or benefits from growing up with smartphones/tablets from a young age are still to be described. This means that there is a great need for a research infrastructure that includes specifically children and young adults. 

At the same time, the new information society also provides completely new possibilities to gather information. NorthPop is the first research infrastructure in Västerbotten solely using web-based questionnaires for data collection – most of the participants answer these on their smartphone rather than on their computer. One research group within NorthPop is studying the parents’ use of the internet and social media. One project group is working together with researchers at the department of computing science to develop a smartphone app that will enable even smoother gathering of information, including data on physical activity directly from the smartphone’s motion sensors. The app will also have functionality to test the children’s neuropsychological abilities.

NorthPop is an important regional research infrastructure investment by Umeå University and has since 2015 received infrastructure grants from the University. We are convinced that NorthPop will develop into a very valuable research resource for Region Västerbotten, for Umeå University and for all of Västerbotten over the coming decades and contribute towards world-leading cutting edge research at Region Västerbotten and Umeå University. We also see great opportunities in connecting with other registers and infrastructures, not least Västerbotten's Health Surveys (VHU) and the demographic database which will enable multi-generational research projects. There are also good possibilities with other linked interventional studies as well as commercial innovation projects such as the above-mentioned smartphone app, pilot project for a digitalized Maternal / Child Healthcare etc.

Management and organisation

The current steering group for the NorthPop infrastructure consists of: professor Magnus Domellöf (chair); associate professor, docent Christina West (vice chair); associate professor Pernilla Lif Holgersson; professor Ingrid Mogren; associate professor, docent Sven-Arne Silfverdal; associate professor, docent Olof Sandström and associate professor Patrik Rydén.

Main contact: Magnus Domellöf, magnus.domellof@umu.se
Data manager: Richard Lundberg, richard.lundberg@umu.se
Website: www.northpop.se

Region Västerbotten is the body in charge both for the biobank (organizationally located under Northern Sweden Biobank) and the database (organizationally located under Register Center North).

The steering committee will be completed with a representative for Region Västerbotten which will be appointed by the Region Västerbotten research and development council (FoU) and a representative for Umeå University, appointed by the university’s Strategic Council for Research and Doctoral Education (FOSTRA).

The steering committee is responsible for the construction of the NorthPop infrastructure and is currently also responsible for data extraction. Once the amount of data and requests for data extraction have increased we plan to create an expert group who will take over the responsibility of dealing with requests for data extraction and requests for biological material. The expert group will be appointed by the Registry and Biobank Consortium (RBKON) https://www.umu.se/en/biobank-research-unit/collaborate-with-us/registry-and-biobank-consortium-rbkon/ which is open to all PhD researchers at Umeå University and Region Västerbotten. This will become an expert group for ‘Children and young adults’ in addition to the existing two expert groups within The Biobank Research Unit which are ‘Cancer’ and ‘Cardiovascular and other diseases’. According to needs, the steering committee and the expert group may be modified further in their composition and organization following requests from Region Västerbotten and Umeå University – it is important to ensure that the organization is transparent, sustainable and future proof.

Availability and data handling

NorthPop is an open infrastructure available to all researchers at Umeå University and Region Västerbotten, as well as external researchers. NorthPop regularly arranges open workshops to which researchers at Umeå University and Region Västerbotten are invited. The purpose of these workshops is to inform about the NorthPop infrastructure and gather proposals for new projects that can make use of the NorthPop database and biobank. Researchers can also at any time contact the NorthPop steering committee with project suggestions.

Applications for data extraction will be sent to NorthPop’s main contact (see above) and will at present be assessed by the NorthPop steering committee – in the future that assessment will be conducted by the RBKON appointed expert group (see above). If the application concerns data extraction, the general rule is to approve it as long as the question is scientifically sound and approval from the Swedish Ethical Review Authority exists. If the application is for access to material from the biobank a separate assessment will be made by the steering committee to ensure that only a minimal amount of sample volume is used for each investigation so that the sample material is not depleted.

Since the NorthPop infrastructure is in the construction phase we do not so far have conventional user fees – we do on the other hand encourage users to apply for grants for NorthPop-related projects and have a demand that a part of any approved research grant is allocated to the NorthPop infrastructure. Once the construction phase is complete and we move towards an operational phase (around 2023-24) this system will be replaced by more conventional user fees.

The NorthPop data manager assists researchers with data extraction. Data storage and data extraction are handled by ICT Services and Register Center North taking into account relevant legislation on protection of sensitive data, including the General Data Protection Regulation (GDPR). Users are normally given access to anonymous data, but some data extraction may include personal identifiable sensitive data if required by the aims of the project and if approval from the Ethical Review Board exists.

Handling and extraction of samples from the biobank is done according to existing routines at the Northern Sweden Biobank.

Examples of research projects based on the NorthPop infrastructure

Can epigenetic modifications be used as markers of chemical exposures, dietary lifestyle, socioeconomic factors and early childhood health?

Sophia Harlid, Dept of Radiation Sciences, Umeå University; Patrik Andersson, Dept of Chemistry, Umeå University; and coworkers

Exposure to environmental pollutants during fetal development may have long lasting health effects. High blood levels of perfluorinated compounds, phthalates and bisphenols in pregnancy have been associated with adverse health outcomes in the child. A potential mediator between exposure and outcome is epigenetic modifications which can potentially prime the individual for future allergy development. It is challenging to determine whether changes to DNA methylation plays a causal role between exposure (environmental pollutants, dietary and lifestyle exposures) and outcome (e.g. asthma and allergies) and requires access to large prospective cohorts with sufficient information on lifestyle, environment and health. One such infrastructure is the newly established NorthPop study – a prospective birth cohort with the goal of recruiting 10 000 pregnant women who will be followed (together with their child) for at least seven years. We intend to use a unique multifactorial and comprehensive approach where we measure environmental pollutants in biological samples in pregnancy, connect these to genome wide DNA methylation patterns in cord blood and use this information to identify epigenetic patterns associated with health in early childhood. We will focus on chemical pollutants previously associated with adverse health outcomes and in-depth information on diet, exercise, socioeconomic status and early childhood health outcomes. Experts from different fields ranging from molecular epidemiology and medicine to environmental chemistry are participating in the study, which utilizes a strong multidisciplinary approach and design.

Programming of the gastrointestinal microbiota and allergic disease within the prospective NorthPop cohort

Christina West, Dept of Clinical Sciences, Umeå University, and coworkers

The “epidemic” of allergic diseases has become a major challenge as 30% of children are affected by some allergic manifestation. Factors that have been associated with early immune dysregulation and allergic disease include microbial and dietary patterns. Our aim is to detail how maternal microbial exposures from multiple body sites influence infant gastrointestinal microbiota establishment, immune development and the risk of allergic disease, with the goal of identifying preventive risk factors. For this, we use the NorthPop infrastructure, where prospective questionnaire and register-based data and biological specimens (cord blood, breast milk, saliva and feces) are collected prospectively from 10 000 mother-partner-child triads and the children will be followed until 7 years of age. Questionnaire data on parents’ health, diet and socioeconomics will be collected in pregnancy. Maternal diet will be mapped with frequency questionnaires. Questionnaire data on child health, morbidity and dietary exposures will be collected at 4, 9 and 18 months, 3 and 7 years. Microbial composition and diversity will be analyzed in maternal blood (buffy coat), placenta, saliva, stool and breast milk; in stool and saliva samples from the child at birth, 1, 9, 18 months, 3 and 7 years using 16S rDNA sequencing. Patterns of plasma cytokines, chemokines and blood microbiota (buffy coat) will be analyzed in cord blood and at 18 months. Vitamin D will be analyzed in maternal, cord blood and infant blood samples. Allergic sensitization will be assessed at 18 months and 7 years. Early onset NCDs often start in childhood and frequently persist into adulthood. This yields a burden for the individual, the family and the healthcare system. We seek to identify both preventable risk factors and risk groups that may be the target for preventive actions in pregnancy and early parenthood. This can have a major impact at both the individual, family and societal level.

Oral microbiota in health and disease

Pernilla Lif Holgersson, Dept of Odontology, Umeå University, and coworkers.

Recent studies show that the oral microbiota is important not only for dental caries and periodontitis, but also conditions like obesity and associated diseases. The overall purpose of this project is to follow development of the oral microbiota using multiplex sequencing of bacterial gene pattern and gene expression in relation to age, environmental exposures, and oral and general health or disease. The study utilizes the large-scale NorthPop biobank. The specific aims are (i) to characterize and follow the development of the oral microbiota from early infancy to late childhood and relate it to mode of delivery, feeding mode, and the oral microbiota of the caregiver and study the stability of the oral microbiota in a short and long term perspective in infancy-childhood, (ii) to characterize the human milk microbiome at various lactation stages and relate it to the natural course of the oral microbiome of the infant, (iii) to link obtained microbiota data with data from the NorthPop cohort and search for associations with development of obesity, immune related diseases, and oral disease. Use of the multiplex NSG methods facilitates both wide and deep characterization at the species level for most members of the oral microbiome, and the PacBio method even clonal distinction as amplicons may be used from different house-keeping genes. The study will add knowledge on how foods and nutritional status may contribute to a healthy oral environment and optimal dental health, and potentially underpin appropriate parental counselling.

Effects of nutrition and other early environmental factors on brain development and cognitive/behavioral problems in children

Magnus Domellöf, Dept of Clinical Sciences, Umeå University, and coworkers.

About 20% of Swedish children are affected by cognitive or behavioral problems (e.g. ADHD), which severely impact their quality of life and frequently persist into adulthood. The brain is the fastest growing organ in the fetus and young child and early nutrition and other environmental factors during fetal life and early childhood are critical for normal brain development. We have previously shown that delayed umbilical cord clamping at birth, iron supplements, as well as provision of specific milk fat components to infants can have significant, positive effects on later cognitive and behavioral function up to school age. Nutrient deficiencies still occur in young children in Sweden and are prevalent especially for some nutrients (iron, iodine, vitamin D, complex lipids) and in some large risk groups (low birth weight children and children of immigrant parents). The study aims to investigate the associations between early nutrient deficiencies (during fetal life and the first postnatal years), brain development and neurodevelopmental outcomes in children with the goal of identifying nutritional interventions which will effectively reduce these common and disabling childhood morbidities. The specific aims are to assess in the NorthPop cohort (n=10 000) associations between serum concentrations of vitamin D, folate, iron, zinc, cholesterol, DHA and other nutrients and nutrition related biomarkers in pregnant women and newborns, and determine whether these deficiencies are associated with lower neurodevelopmental scores during childhood. This project will give the evidence base for future national and international recommendations on early life nutrition and may help reduce the prevalence of cognitive and behavioral problems in children.

Digital media, social support and wellbeing among parents

Anna Baranowska-Rataj, Simon Lindgren, Dept of Sociology, Umeå University and coworkers.

Raising children is often seen as bringing emotional rewards and a sense of personal fulfilment, but it may also undermine wellbeing and lead to stress, anxiety or depression. It places parents under a lot of pressure, as it requires financial expenses, involves substantial reorganization of professional and personal life, leads to time conflicts, sleep deprivation and fatigue, and it often brings tensions in partnership relations. While a large body of research argues that social support from relatives, friends and peer parents may help in coping with some of the challenges related to parenthood, so far little attention has been paid to emerging forms of social support provided online. This project aims at filling this gap by addressing the following research questions: (1) How do parents exchange emotional, informational, and tangible support online? What is the social structure and textual content of interactions that arise in such contexts? (2) How is information and knowledge collectively filtered, interpreted, evaluated, synthesized and used online among parents? To what degree, and how, are shared interests and common experiential themes used to create group cohesion? (3) To what extent can such cohesion form the basis of peer-support strategies, and what are those strategies? What types of social networks are formed online among parents? Does participation persist over time? What is the relationship between giving and receiving peer-support? (4) How does using digital media affect parental wellbeing? For which groups of parents are the effects most pronounced? Research design: The project combines analysis of data from digital media and analysis of data from the NorthPop infrastructure. Information is collected on family members’ background characteristics, lifestyle and health and wellbeing. Our outcome variables measuring parental wellbeing are derived from the General Health Questionnaire. Analyses will also incorporate a set of control variables to reduce confounding bias. This will allow us to quantify the impact of digital media on parental wellbeing and indicate the social categories of parents for whom these benefits are the strongest.

Additional ongoing research projects:

The circadian rhythm of infants in the subarctic region of Västerbotten: Associations between sleeping patterns, feeding patterns, seasonal daylight and health in infants
K Wulff, Dept of Radiation Sciences, Umeå University

Effects of early nutrition, growth and other preventable factors on the risk of overweight and obesity in children
I Öhlund et al, Dept of Clinical Sciences, Umeå University

Acceptance commitment therapy for pregnant women with decreased psychological wellbeing
Stefan Holmström et al, Dept of Psychology, Umeå University

Fetal and early life exposures and the risk of asthma and allergic disease in children
Christina West, Dept of Clinical Sciences, Umeå University

Sustainable physical activity
Anncristine Fjellman-Wiklund, Erik Rosendahl et al. Dept of Social Medicine and Rehabilitation, Umeå University

Complications during pregnancy in association with socioeconomic factors in the county of Västerbotten
I Mogren, I Ohlsson, L Meander, Dept of Clinical Sciences, Obstetrics/Gynecology, Umeå University

Mental well-being and pregnancy-related stress in pregnant women in Västerbotten
M Lind, D Wahlström, E Domellöf, Dept of Psychology, Umeå University

Early childhood neurological development in association to socioeconomic factors a study in the county of Västerbotten
F Berg, M Domellöf, Dept of Clinical Sciences, Umeå University

How can celiac disease be prevented in children?
O Sandström, Dept of Clinical Sciences, Umeå University

Serological biomarkers in allergic diseases and celiac disease
Catharina Eriksson, Dept of Clinical Microbiology, Immunology, Umeå University

NorthPop’s users

PhD researchers who work on projects based on the NorthPop infrastructure, per department at Umeå University:

Clinical Sciences: Magnus Domellöf, Christina West, Sven-Arne Silfverdal, Olof Sandström, Anna Chmielewska (University of Warsaw), Inger Öhlund, Ingrid Mogren, Maria Lindqvist, Eva Henje Blom

Odontology: Pernilla Lif Holgersson, Ingegerd Johansson

Social Medicine and Rehabilitation: Erik Rosendahl, Anncristine Fjellman-Wiklund, Maria Wiklund, Therese Eskilsson, Jonas Sandlund

Radiation Sciences: Sophia Harlid, Katharina Wulff

Chemistry: Patrik Andersson, Åsa Gustafsson (Swetox), Malin Nording (UC Davis)

Sociology: Simon Lindgren, Anna Baratowska-Rataj, Sara Kalucza

Psychology: Stefan Holmström, Eva Palmqvist, Erik Domellöf

Clinical Microbiology: Catharina Eriksson

Public Health and Clinical Medicine: Bo Glas

Mathematical Statistics: Patrik Rydén

Computing science: Helena Lindgren

Contact

Magnus Domellöf
Professor, senior consultant (attending) physician
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Christina West
Associate professor, senior consultant (attending) physician
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Richard Lundberg
Project coordinator
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Ingrid Mogren
Professor, senior consultant (attending) physician
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Pernilla Lif Holgerson
Associate professor, senior consultant dentist
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Sven Arne Silfverdal
Associate professor, senior consultant (attending) physician, timlärare
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Inger Öhlund
Research fellow
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Olof Sandström
Associate professor, senior consultant (attending) physician
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