Nordic Health Registry-Based Research: A Review of Health Care Systems and Key Registries.

The Nordic countries are Denmark, Finland, Iceland, Norway, and Sweden and comprise a total population of approximately 27 million. The countries provide unique opportunities for joint health registry-based research in large populations with long and complete follow-up, facilitated by shared features, such as the tax-funded and public health care systems, the similar population-based registries, and the personal identity number as unique identifier of all citizens. In this review, we provide an introduction to the health care systems, key registries, and how to navigate the practical and ethical aspects of setting up such studies. For each country, we provide an overview of population statistics and health care expenditures, and describe the operational and administrative organization of the health care system. The Nordic registries provide population-based, routine, and prospective data on individuals lives and health with virtually complete follow-up and exact censoring information. We briefly describe the total population registries, birth registries, patient registries, cancer registries, prescription registries, and causes of death registries with a focus on period of coverage, selected key variables, and potential limitations. Lastly, we discuss some practical and legal perspectives. The potential of joint research is not fully exploited, mainly due to legal and practical difficulties in, for example, cross-border sharing of data. Future tasks include clear and transparent legal pathways and a framework by which practical aspects are facilitated.

Application of a novel hybrid study design to explore gene-environment interactions in orofacial clefts.

Orofacial clefts are common birth defects with strong evidence for both genetic and environmental causal factors. Candidate gene studies combined with exposures known to influence the outcome provide a highly targeted approach to detecting GxE interactions. We developed a new statistical approach that combines the case-control and offspring-parent triad designs into a "hybrid design" to search for GxE interactions among 334 autosomal cleft candidate genes and maternal first-trimester exposure to smoking, alcohol, coffee, folic acid supplements, dietary folate and vitamin A. The study population comprised 425 case-parent triads of isolated clefts and 562 control-parent triads derived from a nationwide study of orofacial clefts in Norway (1996-2001). A full maximum-likelihood model was used in combination with a Wald test statistic to screen for statistically significant GxE interaction between strata of exposed and unexposed mothers. In addition, we performed pathway-based analyses on 28 detoxification genes and 21 genes involved in folic acid metabolism. With the possible exception of the T-box 4 gene (TBX4) and dietary folate interaction in isolated CPO, there was little evidence overall of GxE interaction in our data. This study is the largest to date aimed at detecting interactions between orofacial clefts candidate genes and well-established risk exposures.