Blog by: Anna M. Bofin
Professor of Medicine (Pathology)

Breast cancer is a disease of the milk-producing glandular cells, the ductal and lobular cells of the breast. In order to survive, cancer cells need nutrients, support and an environment that they thrive in so that they can grow, multiply and spread. At an early stage, cancer cells establish a close dialog with the tissues and cells that surround them. They encourage blood vessels to develop in order to supply them with glucose and oxygen and they stimulate cells in surrounding tissue, stromal cells, to build a scaffold that can support the growing population of cancer cells.

This close communication between cancer cells and their microenvironment and the ability of cancer cells to remodel their surroundings according to their needs, is acknowledged as a vital part of the development of a tumour.

The normal glandular structures of the breast are embedded in a connective tissue stroma that supports and protects the glands in both the resting state and during lactation. This supportive tissue is part of the dynamic microenvironment of the breast. In breast cancer tumour cells develop the ability to modify the connective tissue cells nearby in order to obtain nutrients and to enable the cancer cells to invade adjacent tissue. Indeed, some tumour cells are so adaptable that they themselves can transform from glandular or epithelial cells into stromal or mesenchymal cells. This phenomenon is called epithelial-mesenchymal transition (EMT) and is essential for the development of a tumour.

Much research is being done on the molecular aspects of tumour development, connective tissue changes and EMT. The Breast Cancer Subtypes research group wanted to investigate whether it was possible to identify any changes in connective tissue fibre patterns within the tumour and at its edge compared to normal tissue.

In collaboration with Associate Professor Magnus B Lilledahl at the Department of Physics, NTNU, the Breast Cancer Subtypes research group decided to study collagen fibre patterns in tissue sample from breast cancer. The work was done by medical students Anders Brabrand and Ian Kariuki as their student thesis, using second harmonic generation laser microscopy.

The study was carried out on a small number of cases of breast cancer, but the complexity of the microscopic examinations and the numbers of images necessary for analysis were considerable.  Brabrand and Kariuki became a regular sight at the Department of Physics as they exploited all available time slots in the lab and they frequently worked hard into the night analysing their results.

The outcome of their work was well worth the effort. They discovered that collagen fibres in the tumour microenvironment undergo different changes dependent on whether they are inside the tumour or at its edge. They found that cancer cells induce structural changes in the stroma that are beneficial to themselves.  In normal tissue the fibres are wavy and look a bit like angels’ hair. In the middle of the tumour, the fibres are very straight but lie in a criss-cross pattern. At the growing edge of the tumour, however, they found that the fibres are parallel to each other making a kind of railway track along which the cancer cells can migrate into the surrounding tissue.

Anders Brabrand og Ian Kariuki, medical students at NTNU

Kariuki and Brabrand were awarded a travel stipend for their work by the Oslo Breast Cancer Consortium (OSBREAC) in 2013 and they used it to participate in the 26^th European Congress of Pathology in London, 2014. Their findings were published this year.

At present Magnus Lilledahl is developing a method that will allow more rapid processing of tissue samples in the laser microscope and the research group plans to study collagen fibre patterns in a larger number of samples of breast cancer. This collaboration between the world of physics and the world of pathology has contributed to our knowledge of the effect of cancer cells on their environment. However, none of it would have been possible without the efforts of two medical students who were willing to give up a good night’s sleep for the sake of science.

 This meeting between the world of physics and the world of pathology could contribute to our knowledge of the effect of cancer cells on their environment.

Blogger: Lars Adde, Paediatric physiotherapist and researcher, NTNU and St. Olavs Hospital

A unique collaboration between a paediatric physiotherapist and a music research provides hope for sick newborsn.

The spontaneous “dancing” movements of infants are telling a story about how healthy they are.

Physiotherapists, doctors, music researchers and mathematicians at NTNU, St. Olavs Hospital and the University of Oslo have recently launched a fruitful, interdisciplinary project. They’re filming and analysing spontaneous movements of infants to try to identify cerebral palsy (CP).

The spontaneous “dancing” movements of infants are telling a story about how healthy they are – or rather how healthy their brains are.

Qualities like the variation and flow of the infants “dancing” movements at the age of 3 months after their due date tell us something about what kinds of injuries the brain has – or has not – sustained.

Physiotherapists and doctors can learn to observe the qualities of movement patterns in premature and sick infants as a sign of possible brain damage and an early marker of cerebral palsy.

Using simple video cameras and newly developed software, the movement patterns in infants can be analysed and quantified.

Cerebral palsy is a physical disability that normally cannot be diagnosed before the child is 1 to 2 years old. This makes it hard to train the brain during the important period between the occurrence of the brain damage (around the time of birth) and the time of diagnosis – which also happens to be the peak period for brain plasticity.

Using simple video cameras and recently developed software, the movement quality of infants can be analysed and quantified. Our team at NTNU and St. Olavs Hospital has for several years researched how the movements of infants can be analysed using video analysis. Music researcher Alexander Refsum Jensenius at the University of Oslo’s Department of Musicology researches music and movement. He has developed a computer programme to analyse and quantify the movement qualities of musicians and dancers.

The software has now been modified and adapted to the movements of infants, and his work has turned into a very fruitful collaboration in which the spontaneous movements of sick newborns are recorded on video, analysed and used to identify cerebral palsy at an early stage.

This picture shows the movement history of one of the infants in the study.

This technology is currently being tested in the US, Turkey, China, India and Norway, focusing on the spontaneous “dancing” movements of infants, computer-based movement analysis and early prediction of cerebral palsy. The project is financed by St. Olavs Hospital and NTNU. national collaborators are the neonatal clinics of OUS, UNN, Levanger Hospital and St. Olavs Hospital.

Learn more about this unique research collaboration on NRK1’s Schrødingers Katt Thursday 16 October (in Norwegian).

Contact: Physiotherapist and researcher Lars Adde, Department of Laboratory Medicine, Children’s and Women’s Health (LBK), NTNU.

Blogger: Vibeke Videm

Twice as many of those who got rheumatoid arthritis between the HUNT2 population-based health survey in 1995-1997 and the next survey (HUNT3) in 2006-2008, reported previous cardiovascular disease at HUNT2. They either had angina or had suffered a myocardial infarction or stroke. The data indicate that there may be a causative link.

(…) chronic inflammation in one part of the body intensifies chronic inflammatory processes in other parts

Atherosclerosis, the most common cause of cardiovascular disease, is caused by chronic inflammation in the vessel walls. Rheumatoid arthritis is due to a gradual process with increasing dysregulation of the immune system that finally leads to inflammation in the joints. The inflammation due to atherosclerosis probably intensifies the process leading to rheumatoid arthritis. The study was recently published in the scientific journal  Arthritis Research and Therapy.

The findings are especially interesting because we already know that persons with established rheumatoid arthritis have an increased risk of cardiovascular disease. Our data indicate that the relationship between rheumatoid arthritis and cardiovascular disease may go both ways: if a person has one of these conditions, the risk of the other increases.

In other words: chronic inflammation in one part of the body intensifies chronic inflammatory processes in other parts. The joints and vessel walls are not independent sites, but influence each other.

In the HUNT surveys, the entire adult population in the county of North Trøndelag in Norway was invited to participate. In HUNT2, 70 % of those invited participated, and in HUNT2, 54 %. We studied 786 participants who reported having rheumatoid arthritis in HUNT3, but not in HUNT2. They were compared to more than 32,000 other HUNT participants. We found that 6.6 % of those who later got rheumatoid arthritis had previous cardiovascular disease, compared to 3.1 % of the other participants.

The risk was now 90 % larger for future rheumatoid arthritis in the participants who had cardiovascular disease at HUNT2.

The diagnosis of rheumatoid arthritis in HUNT is self-reported. This introduces some uncertainty because some of those who answer that they have rheumatoid arthritis may actually have another condition. We therefore repeated the analysis after investigating whether the participants reporting rheumatoid arthritis also had a diagnosis from one of the three hospitals in Trøndelag. When comparing these 201 persons with the remaining HUNT participants the connection became stronger: The risk was now 90 % larger for future rheumatoid arthritis in the participants who had cardiovascular disease at HUNT2.

Approximately 1 % of the population suffers from rheumatoid arthritis. Without treatment, the condition causes pain and gradual joint destruction, resulting in decreased function. To a large extent, this may be prevented by modern treatment. The most important risk factor is a genetic predisposition, and rheumatoid arthritis is more common in women. The risk also increases with advancing age. These are factors the individual cannot influence.

(…) our study confirms that lifestyle-related factors have an important impact on whether a person with a genetic predisposition actually develops rheumatoid arthritis

However, our study confirms that lifestyle-related factors have an important impact on whether a person with a genetic predisposition actually develops rheumatoid arthritis. Smoking, overweight, high blood pressure, too little physical activity and increased blood cholesterol are important risk factors for cardiovascular disease, which in turn is associated with increased risk of rheumatoid arthritis. Several of these factors also directly influence the risk of rheumatoid arthritis, without the “detour” via cardiovascular disease. It is well established that smoking at least doubles the risk of rheumatoid arthritis and that this effect remains for many years following cessation. In our study, the effect from previous cardiovascular disease was additive to the direct effect of smoking.

Which practical conclusions may be drawn from the study?

First, that a person with relatives having rheumatoid arthritis has very strong reasons to try to adopt a lifestyle that reduces the risk of cardiovascular disease: avoid smoking, eat a healthy diet and get enough exercise, and have his or her blood pressure and cholesterol checked from time to time. It is certainly a positive thing that it is possible to do something that reduces the risk of developing disease even if one has had back luck with respect to the genetic predisposition.

(…) a person with relatives having rheumatoid arthritis has very strong reasons to try to adopt a lifestyle that reduces the risk of cardiovascular disease

Second, that someone with cardiovascular disease who develops joint problems may actually have an early form of rheumatoid arthritis, and that the doctor needs to keep this diagnosis in mind during the diagnostic work-up. Joint problems have many causes. But if they turn out to be due to rheumatoid arthritis, it is important to start treatment as early as possible.

International collaboration

The study results from collaboration between researchers at the Medical Faculty at the Norwegian University of Science and Technology in Trondheim, Norway, and researchers at the University of Queensland in Brisbane, Australia. The HUNT study is very well suited for this kind of studies: There are a large number of participants, they represent the general population and not selected subgroups, and follow-up time is long.

We are grateful to the people in North Trøndelag who were willing to participate in several of the HUNT surveys. If not, the study would not have been feasible because it was based on comparison between responses in HUNT2 and HUNT3. The research group is now planning new studies on rheumatoid arthritis in a future HUNT4, where we hope that the inhabitants of North Trøndelag will once again contribute to helping us getting further knowledge about the causes and possible strategies to reduce the risk.

The Gemzell prize at Uppsala University has this year been awarded to Eszter Vanky, researcher at NTNU.

Eszter Vanky, associate professor at the Department of Laboratory Medicine, Children’s and Women’s Healt, received this honor at Uppsala University 20. march 2014 and gave the prestigious “Gemzell lecture of the year”.

Eszter Vanky was nominated for her research in endocrinology, on women with polycystic ovary syndrome (PCOS) and gave a very and interesting lecture at Uppsala University with the title; “PCOS i blant frustrerende, alltid spennande” (PCOS sometimes frustrating, always interesting) . She described for the audience diagnose, pregnancy complications for PCOS-women and treatment in a pedagogic and inspiring way.

Carl Axel Gemzell was an internationally respected Swedish gynecologist and endocrinologist (1910-2007). Gemzell worked in Sweden and USA and contributed significantly to the treatment with gonadotropins to infertile women. He purified protein hormones from pituitaries and introduced stimulation of the ovaries. This was the beginning of assisted human reproduction. He developed several hormone tests, and one of his students developed the modern pregnancy test.

Eszter Vanky receives prize for her research on PCOS

Skilled international researchers has since 1977 been nominated to the Gemzell prize. Only once before has a Norwegian researcher been awarded the Gemzell prize and held the “Gemzell lecturer of the year”. This was Arne Sunde in 2009, also from NTNU.

Eszter Vanky has previously received Norwegian prizes for her research.

During treatment of childhood blood cancer, great variations in side-effects are seen – both in terms of prevalence and seriousness. Some children get more serious side-effects than others. Potentially, the diversity in the toxicity burden for individual patients could reflect the normal genetic variation between patients.

A bone marrow smear at high magnification taken at diagnosis. Most of the blue cells are leukaemic cells. Normal red blood cells are also seen. (Photo: Bendik Lund)

In parallel with the biotechnological development over the last 10-15 years, we have gained extensive knowledge about the normal sequence variation in DNA, which differs from person to person. This sequence variation might explain some of the differences between people, for example height, hair colour, risk of diseases and the body’s reactions to medicines (pharmacogenetics).

There are many types of DNA-variations and one of the most common ones is single nucleotide polymorphism (SNP), where one letter in our genetic code has been replaced by another letter. DNA consists of long chains of base pairs (letters, totalling around 3 billion) and a SNP occurs approximately for every 300th base pair.

We wanted to study what role the natural genetic variation plays in the development of side effects in children treated for leukaemia (cancer of the blood). The most common form of blood cancer in children is acute lymphoblastic leukaemia, and 30-40 children are diagnosed in Norway every year with this type of leukaemia. The treatment consists of chemotherapy given over a period of 2.5 years, and the survival rate today is around 85%. The treatment causes many side effects including reduced immune function and infections. In some cases, the treatment can lead to so serious side effects that the patient dies from the toxicity.

Knowledge about pharmacogenetic variation is already used in the standard treatment for acute lymphoblastic leukaemia when using the chemotherapy 6-mercaptopurine. This drug is dosed based on the patient’s SNP variants for the enzyme that metabolises 6-mercaptopurine (TPMT-genetic variants).

We have collaborated with a research group at the laboratory in Copenhagen (Bonkolab, Rigshospitalet) and, based on existing literature, around 2300 candidate genes that could be significant for children with acute lymphoblastic leukaemia have been identified. Furthermore, the group has made a cost-efficient analysis method where 34,000 genetic variants (SNPs) per patient within these genes (extended candidate gene model) are analysed. Samples from several patients can also be analysed in the same sample tube (multiplexing).

The test tube to the left contains a blood sample from a healthy person. The test tube to the right contains a blood sample form a child with leukaemia. “Leukaemia” means “white blood”, and one can clearly see why when looking at the white layer of cells in the test tube to the right. (Photo: Bendik Lund)

We used this method in a study where we included 69 Danish children with leukaemia and compared the gene variant pattern with clinical data for infections that occurred during the first 50 days of treatment. We identified a SNP profile which with great accuracy can predict the risk for infections in this early phase of the treatment, where many infections are life-threatening.

If these findings are confirmed in similar studies, we may in the future be able to quickly determine whether a patient has an increased risk for serious infections by taking a simple blood test. If the patient is at high risk for serious infections, the treatment could be adapted accordingly for example giving prophylactic antibiotics, or by reducing the intensity of the chemotherapy. Hopefully this will lead to less side effects and higher survival rates.

Further reading:

• Host genome variations and risk of infections during induction treatment for childhood acute lymphoblastic leukaemia
• Risk factors for treatment related mortality in childhood acute lymphoblastic leukaemia

James Paget (photo: wikipedia.org)

“Many of the cells of cancers, for example, may be somewhat like gland cells, yet a practised eye can distinguish them; they are heaped together disorderly and seldom have any lobular or laminar arrangements such as exists in the natural glands or epithelia”

These words were written in 1853 by James Paget who was a surgeon and pathologist, and they describe cancer cells as we see them under the microscope. The cells are different from normal cells. They are mutineers only interested in their own survival at the expense of their host.

To this day, the initial diagnosis of breast cancer is still made by a pathologist examining a tissue sample under a microscope. We know that breast cancers differ greatly in their appearance and that these differences can be explained by differences in their molecular characteristics. These differences are exploited today to give the individual woman a tailor-made treatment based on a set of special tests that have been tried and proven useful for this purpose.

We know that tissue samples from breast cancer harbour even more information that could help us to understand the causes of the disease, determine more effective treatment and avoid overtreatment.

Normal breast tissue (left), breast cancer, ductal type (right)

The Breast Cancer Subtypes research group at NTNU has studied over 900 cases of breast cancer from women in Nord-Trøndelag who took part in a breast cancer screening program organised by the Cancer Registry of Norway over 60 years ago. These women lived in an era before hormone replacement therapy became common and before the implementation of mammography screening. They received limited treatment, often only surgery, making it possible to study the near natural course of this disease.

These samples have now been reclassified into subtypes based on their molecular composition rather that their appearance under the microscope. Follow-up shows that there are differences in survival according to molecular subtype and that most of these differences occur during the first five years after diagnosis. These results were recently published in Breast Cancer Research and Treatment.

Mothers and daughters

Could there be differences in the types of cancer that occur in these two generations?

Like their mothers and grandmothers before them, women in Nord-Trøndelag have continued to contribute to research through their participation in the Nord-Trøndelag Health Study (HUNT). The next step for the Breast Cancer Subtypes research group is to study breast cancer tissue samples from women who took part in HUNT2 between 1995-97. In contrast to their mothers, these women have had access to the contraceptive pill, hormone replacement therapy and mammography screening. Could there be differences in the types of cancer that occur in these two generations?

Breat cancer, lobular type (top left), HER2 protein on the cell membrane (top right), HER2 gene amplification in cell nuclei (bottom left), breast cancer, ductal type (bottom right)

A further question that the Breast Cancer Subtypes group is addressing is survival.

Ultimately, the aim of this work is a better understanding of this complex disease in order to provide the individual woman with a more accurate diagnosis and a more effective treatment of her cancer.

Follow-up over several decades makes it possible to study the molecular characteristics of cancers that have a very good prognosis as well as those with a poor prognosis. Using advanced technology, it is possible to stain and analyse hundreds of tissue samples in a standardised way and study the molecular characteristics of the different cancers. When these data are linked to survival data it will be possible to identify cancers with very good prognosis requiring little or no additional treatment, and others that require individual, tailor-made treatment strategies based on the characteristics of the individual cancer.

Ultimately, the aim of this work is a better understanding of this complex disease in order to provide the individual woman with a more accurate diagnosis and a more effective treatment of her cancer.

Preterm children often have a reduced working memory capacity, which makes it more difficult to learn new things and overcome everyday challenges. But what if playin gcomputer games could improve their working memory?

Our research group at NTNU and St. Olavs Hospital decided to explore whether a computer-based training programme could help a group of severely premature nursery school children with a birth weight of below 1500 grams with their memory and even other cognitive skills.

Computer games improved children’s working memory. (Photo:  Screen dump Cogmed©)

After 5 weeks of training, the children achieved better results on tests focusing on their working memory. They also got better scores for other cognitive skills that are essential for their ability to learn, memorise and pay attention at school.

After 5 weeks of training, the children achieved better results on tests focusing on their working memory.

Premature children are more likely to develop neurological disorders than children born at term. Moreover, they often have reduced concentration skills and working memory capacity compared to children born on or after their due date.

These are all skills we need to be able to learn, plan and solve problems in everyday life. Problems with these skills can therefore have serious consequences fo the child, both socially and in terms of learning disorders and accomplishments at school, which in turn can have negative consequences that last well into adulthood.

Recent studies show that our working memory can be improved through training, and a computer-based training programme developed at Karolinska Institutet in Stockholm has previously shown promising results on children with ADHD and teenagers who were prematurely born with a very low birth weight.

Recent studies show that our working memory can be improved through training.

Our study included 20 preschool children aged 5 to 6 years with a birth weight of below 1500 grams (3.3 pounds). The children used the programme to train at home for 10 to 15 minutes per day, 5 days a week for a total of 5 weeks.

The programme is set up like a computer game where the children visit an amusement park with 7 different rotating exercises (Image 1). The child sees an  image on the computer screen showing a few dots of wool with friendly faces appearing in a specific order (Image 2). Afterwards, the child has to remember the sequences and click on the same dots of wool in the correct order.

Dots of wool with friendly faces enjoy the swimming pool. (Photo: Screen dump Cogmed©)

The programme is designed to increase the difficulty as the child gets better and is able to correctly remember several sequences in a row.

All the children took a series of neuropsychological tests before and after their training. Parents also responded to questions about their children’s adaptive function, anxiety and symptoms of attention disorders, both before and after the training.

After the training, the premature preschool children showed an improvement in results on both prepared and non-prepared working memory tests. They also displayed a clear, positive effect in terms of auditory/phonological attention – which is important for language skills that, in turn, are important in learning and developing reading and maths skills – as well as in visual and verbal memory. 

This appears to show that training the working memory can have an effect on other cognitive functions as well..

Our study was performed on a relatively small number of children, which means that larger studies must be performed before we can give specific recommendations for working memory training in preschool for severely premature children.

Nevertheless, our results are a good indicator that introducing a computer-based working memory programme at preschool age may help preterm children with a birth weight of below 1500 grams. This training can possibly reduce cognitive problems, which could affect future education and working life.

Most women give birth naturally and without problems, but sometimes labour becomes prolonged. Common causes are weak contractions, the position of the baby, or that the baby is too large for the mother’s pelvis. Traditionally the midwives and doctors assess the progression of labour using their hands. Ultrasound is mostly used for check-ups during pregnancy, and seldom used during labour itself.

We therefore wished to investigate whether ultrasound could be a useful tool during prolonged labour.

A hundred-and-ten first-time mothers at Stavanger University Hospital where examined using ultrasound during labour in the period 2009-2010. We studied whether the level and rotation of the baby’s head in the pelvis could predict the probability of normal delivery or caesarean. Ultrasound was compared with traditional clinical examinations.

In the first study we found that there was a great chance of caesarean if labour stopped when the head was high up in the birth canal, but if the head had passed the mid-section of the canal (the tightest part), 90% of the women had a normal delivery. Ultrasound could predict the progression of labour better than traditional clinical examination.

In the second study, two and three dimensional (2D vs. 3D) ultrasound techniques were compared. The results showed that 2D and 3D were equally good techniques. 3D examinations, however, are more complicated and the equipment more expensive, and therefore 2D could be favoured as a simple method giving good information directly in the delivery room.

The rotation of the baby’s head in the pelvis during labour was estimated using ultrasound in the third study. Rotation is necessary for the baby to pass through the birth canal. The study showed that the rotation of the head alone could not predict caesarean vs. vaginal birth. This is probably because the head has to rotate no matter the outcome.

We studied four suggested ultrasound methods to measure the head’s level. The results showed that they corresponded well, and that all four were better than standard clinical examination.

From this we conclude that ultrasound can be a useful tool during delivery. The ultrasound examination is also more objective than clinical examinations, and ultrasound can help decide who needs a caesarean and when.

Erik Andreas Torkildsen’s viva on the subject takes place on 20. September at 12.14, at Stavanger University Hospital. The trial lecture “The control of labour – contemporary science” will be held at 10.15 the same day.

Torkildsen’s main supervisor has been Torbjørn M. Eggebø (Stavanger) and the second supervisor has been professor Kjell A. Salvesen (NTNU, Trondheim).

The project has been a collaboration between the Women’s clinic in Stavanger and the National Centre for Foetal Medicine, St. Olavs Hospital, Trondheim.

We have known for some time that genetics play a great part in the risk for developing ankolysing spondylitis (Bekhterev’s disease), which leads to inflammation causing pain and stiffness of joints – especially in the back and pelvis. Through an international research collaboration studying genetic material from more than 10,000 patients with ankylosing spondylitis, 13 new genetic loci have been identified that affect the risk for the disease. This is a doubling of the number of known genetic risk loci. The results have recently been published in the journal Nature Genetics.

From the 70s it has been known that almost all patients with ankylosing spondylitis have a genetic variant called HLA-B27.

An Australian research group lead by Professor Matthew Brown at the University of Queensland in Brisbane, Australia, was very positive to including patients from the Nord-Trøndelag health study (HUNT) in Norway. Through the questionnaires from HUNT, we have access to far more information about lifestyle factors than what is common in such international genetic studies. As only a fraction of those with the genetic disposition for ankylosing spondylitis actually develop the disease, we believe that lifestyle factors may also affect the risk. We are therefore now conducting follow-up studies on the HUNT data to investigate this connection further.

The HUNT participants have given us an invaluable contribution, for which we are very grateful.

The fact that so many people from the county of Nord-Trøndelag have contributed to HUNT, and done so repeatedly, means we have data on the impact of changes in lifestyle factors over long periods. The HUNT participants have given us an invaluable contribution, for which we are very grateful. We are now counting on HUNT4 taking place, and hope for an equal willingness to contribute.

From the 70s it has been known that almost all patients with ankylosing spondylitis have a genetic variant called HLA-B27. The connection between ankylosing spondylitis and HLA-B27 is actually one of the strongest known genetic associations for common diseases where more than one gene plays a part. The knowledge of several more risk genes forms the basis for the development of new medication which can slow the inflammation by affecting the underlying mechanisms.

Researchers from 17 countries in Europe, East Asia, North America, Australia, New Zealand and Latin America have collaborated on the new study. Because the impact of each individual genetic risk variable is small and the interaction between them is complicated, we need very large patient numbers to establish clear patterns. This underlines the benefit of international collaboration – this type of knowledge is impossible to obtain through single group efforts.