Examples of Nordic collaborations: benefits and challenges

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1 Examples of Nordic collaborations: benefits and challenges There are numerous well working ongoing Nordic research collaborations, and some Nordic organizations that have a long track record of systematic collaboration, such as for instance the Nordic Cancer Union (NCU) and corresponding organizations in other fields. The following examples intend to illustrate some of the benefits and the challenges (Examples 1-3), and some of the hitherto untapped potential (Example 4), of Nordic collaborations in the health and welfare field. Example 1. The use of SSRIs during pregnancy and adverse effects in the offspring A Nordic collaboration has been established to study possible adverse effects of the use of Selective Serotonin Reuptake Inhibitors (SSRIs) during pregnancy. The study is a joint venture between researchers from the 5 Nordic countries. Depression during pregnancy occurs frequently and estimated rates vary from 7 to 25% and more severe forms of depression will require additional treatment with antidepressants such as SSRIs. Knowledge concerning adverse fetal effects of SSRIs is limited. Though most previous studies found no statistical significant increased risks for congenital malformations in users of SSRIs, there are some alarming findings, and more research within this field is needed. To assess possible risks of SSRIs during pregnancy concerning congenital malformations and PPHN large population based studies with valid and prospectively collected data and clearly stated hypotheses are required. The Nordic countries with a genetically and socio-economically homogeneous population of more than 25 million people have excellent opportunities to perform such studies. Increased knowledge concerning possible adverse effects of SSRIs to the fetus will promote safe and rational use of SSRIs during pregnancy. Data was obtained from the Prescription Registers, Medical Birth Registers, Causes of Death Registers, the Malformation Register in Finland, the Abortion Registers in Denmark and Finland, the Patient Registers in Denmark, Iceland, Sweden and Finland, The Danish Psychiatry Register, and include pregnant women in the registers from 1994 to Data sampling are performed in each country and decoded data exported to Karolinska Institutet in Sweden for further analyses. As Danish prescription data can only be obtained at site (Statistics Denmark), the Danish Maternal Medicines file was added at a later stage and after pooling of all other data. The team at KI merged data from all the countries and forward the data set to Statistics Denmark for inclusion of Danish prescription data (Danish Maternal Medicines file) and for on-line analyses to a server placed at Statistics Denmark. Previous studies have been hampered by recall bias and low statistical power. This study has good statistical power (1.6 million pregnancies) and valid information on exposure and outcomes. The large number of observations enables the separate analyses of each SSRI substance. The large numbers of pregnant women needed to assess adverse outcomes of drug exposures during pregnancy is not feasible in RCTs conducted before the drug is on the market. The research network of experiences and expertise that have been built up in this first Nordic collaborative study on adverse effects on drugs in pregnancy will be valuable in facilitating future Nordic collaborative studies of this kind.

2 One of the main concerns expressed by the researchers is time-delay. The final protocol for this collaboration was agreed upon in November The data was planned to be ready for transferring to Karolinska during June However, the data was delayed in most of the countries. In October 2010 the main data files were ready for analyses. However, data of malformations from Finland were sent to Karolinska as late as March The first article was submitted in March The researchers further express concerns about the fact that Statistics Denmark does not make prescription data available for use outside the institution. New rules for access to micro data were introduced in All data processing is actually done in Statistics Denmark. Data cannot be transferred from Statistics Denmark to the researcher s computer but are analyzed using a secure, encrypted Internet connection. The conditions in DK with no disclosure of individual data on drugs, which require all data to be transferred to Statistics Denmark, requires IT skills to the institution seeking access and that the Danish research partner is alert (it takes time to get permits and make it all work). This contributes to further delays (data to be sent to administrators in Statistics Denmark which put them into the project file). The researchers suggest that if other countries choose to be on a similar system as DK it will be the end of Nordic registry linkages. The researchers points to the importance of showing the different conditions in the Nordic countries and of having a national PI who know the rules. They also suggest that an important prerequisite for successful cooperation is that the research team gets along and knows each other a bit in forehand, and that a common framework for analyzing Nordic prescription data would be desirable and do projects more successful in the future.

3 Example 2. Costs of cancer in the Nordic countries Cancer rates in the Nordic countries are rising and will continue to do so in the coming years due to ageing and increasing population sizes. The cancer-burden levies major tolls on patients and their families in terms of disability and premature mortality. It also incurs high costs on the societies at large. The study provides estimates and comparison of costs of cancer, applying a common approach and methodology, in all of the Nordic countries. It covers costs of hospital treatment, prescription drugs, and screening programs (for breast and cervical cancer) (health care costs); and public expenditures related to sickness absenteeism and early retirement (income loss compensation payments ILCP). The study is initiated and financed by the Nordic Cancer Union (NCU). The work is performed in collaboration of participants of all six Nordic countries. For NCU the contractor is the Norwegian Cancer Society. SINTEF is the contractor for the participating parties in the study consortium, with the National Institute for Health and Welfare (THL), Applied Health Economics Sweden AB, Dansk Sundhedsinstitut (DSI), Landspítali- National University Hospital of Iceland and Ministry of Health Affairs, Faroe Islands as subcontractors. For policy and planning purposes it is of interest to know: What is the magnitude and what are the characteristics of cancer costs? Are there differences between cancer sites? If so, how do these differences influence future challenges? The Nordic countries share major similarities in regard to their political systems, welfare systems and health care systems. Hence, knowledge about cost differences and factors influencing these, are of interest for policy development and planning at the national level. The comparative aspect adds additional insight: To what extent and why do cancer costs vary between the Nordic countries? Cost data were obtained from national patient registers (data on hospital stays and outpatient visits), national pharmaceutical registers (prescription drugs), national cancer registries (screening activities), social insurance institutions (publicly refunded sickness benefits, publicly paid disability pensions) and national bureaus of statistics (demographic data). Finally, prevalence data were obtained from the database in the NORCAN project. Comparison of the costs of cancer between nations is of great value for policy making and planning of services. The Nordic cancer registries provide comparable and valid prevalence data, which, when combined with the cost data, offer each nation an opportunity to compare their expenditures to those of other nations. Such a comparison can guide nations in their policy formation as it pertains to funding of cancer services and allocations of funds to the various treatment options and patient groups. Due to the high level of quality of data in the Nordic cancer registries and the national bureaus of statistics no major difficulties were associated with the prevalence data or demographic data. The most important difficulties in the study were associated with the availability of cost data and comparability of cost data between the nations. The granularity and specificity of the cost data varied from one nation to another as well as between individual registries in each country. The differences in the funding of health care and the methods used in reimbursing providers and patients for their expenses also required

4 some assumptions and adjustments in the data preparation process. This may have resulted in some misclassifications and biases.

5 Example 3. The SCANDAT database The Scandinavian Donations and Transfusions (SCANDAT) database holds data on virtually all blood donors and recipients who have been registered at least once in any of the computerized local blood bank databases in Sweden and Denmark. Computerizations of administrative transfusion registers were initiated in 1966 in Sweden and in the 1980 s in Denmark and today these registers cover both countries completely. All individuals in these registers are uniquely identifiable through their 10-digit National Registration Numbers (NRN) in Sweden or 10-digit Civil Registration Numbers (CRN) in Denmark. As these identification numbers are used in all contacts with the health care system and in all population and health registers it was possible to link data from the local blood banks with national population and death registers as well as with the national inpatient, cancer and cause of death registries. Where applicable, these linkages provided dates of emigration, dates and causes of death, clinical data on all incident malignancies as well as information on hospitalizations since 1968 in Sweden and since 1977 in Denmark. Currently the SCANDAT database contains data collected over a period of 34 years between 1968 and 2002 on 15 million donations made by 1.1 million blood donors and almost 12 million transfusions administered to 1.3 million recipients. Altogether, 13 papers have so far been published from the SCANDAT project group. Initially the SCANDAT database was created primarily for very specific research purposes, to study cancer incidence in blood donors and transfusion recipients, and to investigate the possibility that cancer can be transmitted via blood transfusions. The SCANDAT database has been used for six studies of mortality and cancer patterns in blood donors and recipients in general and one study of potential transmission of cancer from donor to recipient. On a separate, but related track, the database was used to show for the first time how anemia develops in the early, pre-diagnostic stages of malignant disease. Recently, the research emphasis of the database has shifted to clinical nuances of blood transfusions, including studies of the health effects of long-term storage of red-cell concentrates, the association between plasma donor blood group characteristics and recipient survival and of mortality in recipients of plasma from female donors compared with recipients of plasma from male donors. To ensure continued actuality the SCANDAT database is currently being updated with data for the period from Swedish and Danish blood banks and from health registers. Future research plans include studies of donor-specific risk factors for non-infectious transfusion complications in recipients. These studies will take advantage of the very unique capacity of the SCANDAT database to connect individual donor and blood products with individual recipients on a large scale. The register data will be combined with measures in biological samples. The uniqueness and potential of the SCANDAT database has been acknowledged in an editorial accompanying one of the papers from the group. The editorial highlights the importance of linking databases from Denmark and Sweden, because it provides the ability to validate diseases from one country with that from the other. It proceeds to suggests that the value of examining associations in two different (albeit similar) settings and healthcare systems not can be overstated, and that it will be important to explore the potential for adding more countries to this linked donor/recipient/health outcome data set, or create similar registers in other regions of the world.

6 One of the major challenges of putting together the SCANDAT database was that not all blood banks collect the same information and the formatting of the data varies between blood banks. Extensive data remodeling has thus been necessary. In order to create a database that was compatible with the existing material a survey was made among the key individuals responsible for computer systems in all Swedish and Danish transfusion medicine clinics and blood banks. These persons were asked what data was recorded, how it was stored, in what formats and in what volumes. Based on this information a database model containing all universally available data of interest to the project was constructed. Another challenge was that some of the earliest data was not available on modern medium. The blood banks did no longer have the necessary equipment to read this data and outside expert help was required.

7 Example 4. The Pandemic Influenza vaccine and narcolepsy - a potential collaboration After the influenza A(H1N1) pandemic in 2009/2010, concerns have been raised about a potential causal link between the Pandemrix vaccine and narcolepsy, especially in children. In Sweden, Finland and Norway, there have been reports of an increased incidence of narcolepsy, and several cases have been reported to medical agencies as adverse events after vaccination. However, narcolepsy is a rare diagnoses and it is a challenge to obtain correct information on all new cases of narcolepsy, both vaccinated and unvaccinated. Increased awareness may increase reporting in vaccinated children more than in unvaccinated children. As infections are known to trigger neurological conditions, it is important to obtain information on influenza infection in children with neurological symptoms such as narcolepsy occurring after the pandemic. At present there is not sufficient information to conclude if there is a causal relationship between the vaccination and narcolepsy. To assess possible risks of narcolepsy in relation to Pandemrix vaccination large population based studies with valid and prospectively collected data on vaccination status and influenza infection are required. Several of the Nordic countries achieved high influenza vaccination coverage during the Pandemic, and for a substantial part of the Nordic population, vaccination with Pandemrix was registered. There is a great need for studies that may clarify the suggested association between vaccination and narcolepsy, especially studies elucidating bias in reports of narcolepsy cases and also investigate a possible role for influenza infection in patients developing narcolepsy. In Norway, the Norwegian Institute of Public Health has already started a study (called RegFlu) using national registries to investigate the association between vaccination and narcolepsy. Experiences from this study will be useful in further planning of the Nordic collaboration. Relevant data in studies of narcolepsy are registries where narcolepsy diagnoses may be collected, such as patient registries/hospital data in the patient registries in Norway, Denmark, Iceland, Sweden and Finland. Other relevant registries include prescription registries, vaccination registries, surveillance data on contagious diseases, and other data on influenza infection (primary health care databases or other). Data sampling can be performed in each country and decoded data exported to one Nordic institution for analyses. The signal of narcolepsy in children vaccinated with Pandemrix is of great concern. Reports and studies so far have had low statistical power and may be biased due to increased awareness in vaccinated persons. This may lead to a possible skewed case-finding as vaccinated cases may have been easier to identify and include than non-vaccinated cases. Since narcolepsy is such a rare condition, a collaboration between the Nordic countries with registries covering large populations will increase the possibility to detect associations and clarify if there has been an increase in narcolepsy related to vaccination with Pandemrix. There are several challenges related to a collaboration in narcolepsy studies. The registration of vaccinations and narcolepsy diagnoses vary in the Nordic countries. There is a time lag from early symptoms to final diagnoses, and the time and criteria to obtain a diagnosis in a registry may vary between countries. Also, information on influenza infections may not be available in all countries. In addition, there are legal and technical challenges related to data transfer and analyses, with different legislation and procedures within each relevant registry and within each country.