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1.  Preterm birth and unintentional injuries: risks to children, adolescents and young adults show no consistent pattern 
Preterm birth is associated with a number of physical and mental health issues. The aim of this study was to find out if there was also any association between individuals born preterm in Sweden between 1984 and 2006 and the risk of unintentional injuries during childhood, adolescence and young adulthood.
The study followed 2,297,134 individuals, including 5.9% born preterm, from 1985 to 2007 for unintentional injuries leading to hospitalisation or death (n=244,021). The males and females were divided into four age groups: 1–5 years, 6–12 years, 13–18 years and 19–23 years. Hazard ratios were calculated for falls, transport injuries and other injuries.
After adjusting for a comprehensive set of covariates, some of the preterm subgroups demonstrated slightly increased risks of unintentional injuries, while others showed slightly decreased risks. However, most of the estimates were borderline or non-significant in both males and females. In addition, the absolute risk differences between individuals born preterm and full term were small.
Despite the association between preterm birth and a variety of physical and mental health consequences, this study shows that there is no consistent risk pattern between preterm birth and unintentional injuries in childhood, adolescence and young adulthood.
PMCID: PMC3566316  PMID: 23181809
accidents; adolescence; childhood; preterm birth; injuries
2.  Determination of 14 Circulating microRNAs in Swedes and Iraqis with and without Diabetes Mellitus Type 2 
PLoS ONE  2014;9(1):e86792.
Recent reports suggest that immigrants from Middle Eastern countries are a high-risk group for type 2 diabetes (T2D) compared with Swedes, and that the pathogenesis of T2D may be ethnicity-specific. Deregulation of microRNA (miRNA) expression has been demonstrated to be associated with T2D but ethnic differences in miRNA have not been investigated. The aim of this study was to explore the ethnic specific expression (Swedish and Iraqi) of a panel of 14 previously identified miRNAs in patients without T2D (including those with prediabetes) and T2D.
A total of 152 individuals were included in the study (84 Iraqis and 68 Swedes). Nineteen Iraqis and 14 Swedes were diagnosed with T2D. Expression of the 14 selected miRNAs (miR-15a, miR-20, miR-21, miR-24, miR-29b, miR-126, miR-144, miR-150, miR-197, miR-223, miR-191, miR-320a, miR-486-5p, and miR-28-3p) in plasma samples was measured by real-time PCR.
In the whole study population, the expression of miR-24 and miR-29b was significantly different between T2D patients and controls after adjustment for age, sex, waist circumference, family history of T2D, and a sedentary lifestyle. Interestingly, when stratifying the study population according to country of birth, we found that higher expression of miR-144 was significantly associated with T2D in Swedes (OR = 2.43, p = 0.035), but not in Iraqis (OR = 0.54, p = 0.169). The interaction test was significant (p = 0.017).
This study suggests that the association between plasma miR-144 expression and T2D differs between Swedes and Iraqis.
PMCID: PMC3907562  PMID: 24497980
3.  Effects of prescribed antithrombotics and other cardiovascular pharmacotherapies on all-cause mortality in patients with diabetes and atrial fibrillation – a cohort study from Sweden using propensity score analyses 
To study mortality rates among patients with diabetes and concomitant atrial fibrillation (AF), prescribed different cardiovascular drugs in primary health care.
Study population consisted of men (n = 1319) and women (n = 1094) aged ≥45 years from a database including 75 primary care centres in Sweden. Cox regression analysis, with hazard ratios (HRs), 95% confidence interval (95% CIs) and mortality (years to death) as outcome, and Laplace regression, with difference in time to first 10% mortality (with 95% CI), were performed. Independent variables were prescribed cardiovascular drugs. Regression models were adjusted for a propensity score calculated separately for each prescribed drug class (comprising age, cardiovascular co-morbidities, education, marital status and pharmacotherapy).
Overall mortality was lower in the whole sample for anticoagulants vs no treatment (HR 0.45; 95% CI 0.26-0.77); and among patients < 80 years for anticoagulants vs. antiplatelets (HR 0.44; 95% CI 0.25-0.78); while among individuals aged ≥80 years, antiplatelets (HR 0.47; 95% CI 0.26-0.87) and anticoagulants (HR 0.49; 95% CI 0.24-1.00) vs. no treatment were equally effective. Statins were associated with lower mortality among those <80 years (HR 0.45; 95% CI 0.29-0.71). Laplace regression models in the whole sample, with years to first 10% of total mortality as outcome, were significant for: among patients < 80 years anticoagulants vs. no treatment 2.70 years (95% CI 0.04-5.37), anticoagulants vs. antiplatelets 2.31 years (95% CI 0.84-3.79), and those ≥80 antiplatelets vs. no treatment 1.78 years (95% CI 1.04-2.52).
Our findings suggest that antiplatelets could exert a beneficial effect among those above 80 years.
PMCID: PMC3892066  PMID: 24397919
Antithrombotic drugs; Statins; Pharmacotherapy; Mortality; Follow-up
4.  A healthy diet with and without cereal grains and dairy products in patients with type 2 diabetes: study protocol for a random-order cross-over pilot study - Alimentation and Diabetes in Lanzarote -ADILAN 
Trials  2014;15:2.
Research on the role of nutrition in type 2 diabetes has largely focused on macro/micronutrient composition and dietary fiber intake, while fewer studies have tested the effects of differing food choice. Some observational studies and short-term intervention studies suggest that a food pattern mimicking the diet with which humans evolved positively influences glucose control and associated endocrine systems. Such a food pattern mainly differs from other common healthy food patterns in its absence of cereal grains and dairy products. The primary aim of this pilot study is to determine the effect of two healthy diets with or without cereal grains and dairy products on glucose control, while keeping participants’ weight stable and other food parameters, such as macro/micronutrient composition, dietary fiber and glycemic load, the same in both diets.
We intend to include 15 adult patients with a medical diagnosis of type 2 diabetes mellitus with or without medication and with an increased waist circumference (≥ 80 cm for women and ≥ 94 cm for men) in a random-order cross-over diet intervention study during two periods of four-weeks separated by a six-week washout period. Patients will be instructed to eat two healthy diets according to official dietary guidelines with respect to macro/micronutrient composition and fiber content, but differing in the type of food included, with one diet being without cereal grains and dairy products. Lunch will be served in a hospital kitchen for control of nutrient intake, while the rest of the meals will be eaten at home according to specific directions. The energy content of the diets will be individually adjusted to maintain a stable body weight during the two four-week intervention periods. Primary outcomes will be change in fasting plasma glucagon and fructosamine, while secondary outcomes include change in fasting glucose and glycated hemoglobin, glucose and glucagon response during oral glucose tolerance test, blood lipids, blood pressure, C-reactive protein, body composition, quality of life, subjective experience with the two diets, satiety scores and changes in medication.
Using these results, we will assess the need to conduct larger and longer studies with similar design.
Trial registration
This trial was registered at as NCT01891955 and Spanish Agency of Medication and Sanitary Products (AEMPS) registration code: MFV-ADI-2013-01.
PMCID: PMC3884016  PMID: 24383431
Protocol; Random-order cross-over trial; Type 2 diabetes mellitus; Metabolic diseases; Dietary intervention; Grain-free diet; Dairy-free diet; Glucagon; Fructosamine
5.  Perinatal and Family Risk Factors for Hodgkin Lymphoma in Childhood Through Young Adulthood 
American Journal of Epidemiology  2012;176(12):1147-1158.
The incidence of Hodgkin lymphoma has increased among adolescents and young adults in recent decades, but the relevant risk factors in early life are still unknown. A national cohort study was conducted of 3,571,574 individuals born in Sweden in 1973–2008 and followed up for Hodgkin lymphoma incidence through 2009, to examine perinatal and family risk factors for Hodgkin lymphoma in childhood through young adulthood (ages 0–37 years). There were 943 Hodgkin lymphoma cases identified in 66.3 million person-years of follow-up. High fetal growth was associated with an increased risk of Hodgkin lymphoma after adjustment for gestational age at birth and other potential confounders (Ptrend = 0.005). Family history of Hodgkin lymphoma in a sibling or parent also was strongly associated with an increased risk, with adjusted hazard ratios = 8.83 (95% confidence interval: 3.67, 21.30) and 7.19 (95% confidence interval: 3.58, 14.44), respectively. No association was found between gestational age at birth, birth order, twinning, parental age, or parental education and Hodgkin lymphoma. These findings did not vary by age at Hodgkin lymphoma diagnosis. Similar associations were found for nodular sclerosis and mixed cellularity subtypes. These findings suggest that perinatal factors including possible growth factor pathways may contribute to the risk of Hodgkin lymphoma in childhood through young adulthood.
PMCID: PMC3571233  PMID: 23171883
birth order; family; fetal development; gestational age; Hodgkin disease; lymphoma; maternal age
6.  The association between cytokines and insulin sensitivity in Iraqi immigrants and native Swedes 
BMJ Open  2013;3(11):e003473.
To investigate the associations between cytokines and insulin sensitivity in Swedish residents born in Iraq and Swedish residents born in Sweden.
Cross-sectional study.
Iraqi and Swedish origin residents of Rosengård area of Malmö, aged 45–65 years, were randomly selected from the census register.
194 (Iraqi, n=107; Swedish, n=87) participants agreed to participate in the study. Nineteen participants dropped out (Iraqi, n=11; Swedish, n=8). Participants who had already been diagnosed with type 2 diabetes mellitus (T2DM), those who could not participate in an oral glucose tolerance test and those who had a cold/fever at the time of blood sampling were excluded. In total, serum samples from 135 individuals of Swedish (n=62) and Iraqi (n=73) origin were included. Serum concentrations of a panel of 10 cytokines, comprising interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12 (p70), IL-13, interferon-γ and tumour necrosis factor-α were analysed by Luminex multiplex assay.
In the whole study population, levels of all tested cytokines were inversely associated with insulin sensitivity index (ISI), independent of age, sex, body mass index (BMI), sedentary lifestyle and family history of T2DM (p ≤ 0.05). Interestingly, stratification of the study population according to country of birth showed a significant inverse association between all tested cytokines and ISI in the Iraqi-born population (p ≤ 0.01). The association was independent of age, sex, BMI, sedentary lifestyle and family history of T2DM. In contrast, with the exception for IL-6 (p=0.05), no other tested cytokine was found to be significantly associated with ISI in the Swedish-born population (p≥0.05).
Our results show an association between cytokines and ISI in the Iraqi-born population but not in the Swedish-born population.
PMCID: PMC3845052  PMID: 24293202
Diabetes & Endocrinology; Molecular Biology
7.  Longitudinal age-and cohort trends in body mass index in Sweden – a 24-year follow-up study 
BMC Public Health  2013;13:893.
The aim of this longitudinal study was to analyze whether mean Body Mass Index (BMI), assessed at four occasions, changed within different age groups and birth cohorts over time, i.e., between 1980/81 and 2004/05, after adjustment for possible confounders.
A sample of 2728 men and 2770 women aged 16–71 years at study start were randomly drawn from the Swedish Total Population Register and followed from 1980/81 to 2004/05. The same sample was assessed on four occasions during the 24-year study period (i.e., every eighth year). The outcome variable, BMI, was based on self-reported height and weight. A mixed model, with random intercept and random slope, was used to estimate annual changes in BMI within the different age groups and birth cohorts.
Mean BMI increased from 24.1 to 25.5 for men and from 23.1 to 24.3 for women during the 24-year study period. The annual change by age group was highest in the ages of 32–39, 40–47 and 48–55 years among men, and in the ages of 24–31, 32–39, and 40–47 years among women. The highest annual changes were found in the youngest birth cohorts for both men and women, i.e., those born 1958–65, 1966–73, and 1974–81. For each birth cohort, the annual change in BMI increased compared to the previous, i.e., older, birth cohort. In addition, age-by-cohort interaction tests revealed that the increase in BMI by increasing age was higher in the younger birth cohorts (1966–1989) than in the older ones.
Public health policies should target those age groups and birth cohorts with the highest increases in BMI. For example, younger birth cohorts had higher annual increases in BMI than older birth cohorts, which means that younger cohorts increased their BMI more than older ones during the study period.
PMCID: PMC3849274  PMID: 24074433
Age; Birth cohort; Body mass index; Longitudinal data; Mixed models
8.  Incidence of hereditary amyloidosis and autoinflammatory diseases in Sweden: endemic and imported diseases 
BMC Medical Genetics  2013;14:88.
Amyloidoses are a heterogeneous group of progressive diseases caused by tissue deposition of misfolded proteins. According to the International Classification of Diseases, hereditary amyloidosis is divided into neuropathic and non-neuropathic forms. In Sweden, neuropathic heredofamilial amyloidosis has been identified as familial amyloidotic polyneuropathy (FAP), a fatal disease that is treated by liver transplantation. The non-neuropathic form includes familial autoinflammatory diseases. As no incidence data on these hereditary diseases are available and as even diagnostic data on non-neuropathic forms are lacking we determined the incidence of these diseases and characterized non-neuropathic conditions.
Patients were identified using data from the Swedish Hospital Discharge Register and from the Outpatient Register for 2001 through 2008. All patients discharged with hereditary amyloidosis diagnoses were included and standardized incidence rates were calculated.
Non-neuropathic disease was diagnosed in 210 patients, with an incidence of 2.83 per million. FAP was diagnosed in 221 patients, with an incidence of 2.02 per million. Two northern provinces that are home to 5% of the Swedish population accounted for 77% of FAP cases; the incidence in one of them, West Bothnia, was 100 times that in the rest of Sweden. Approximately 98% of non-neuropathic disease patients were immigrants, most of whom were from the Eastern Mediterranean area. Young Syrian descendants had the highest incidence rate, which was over 500-fold higher than that in individuals with Swedish parents. Even the early onset of these conditions identified them as familial autoinflammatory diseases.
FAP cases were highly concentrated in the two northernmost provinces. Non-neuropathic familial autoinflammatory diseases were of early-onset and immigrant origin most likely related to periodic fever syndromes. Paradoxically, FAP has remained endemic, in spite of population movements within the country, while familial autoinflammatory diseases, with an incidence exceeding that of FAP, were brought into the country as a result of immigration mainly from the Eastern Mediterranean area.
PMCID: PMC3766062  PMID: 24138840
Hospitalization; Heritable amyloidosis; Periodic fever syndrome; Mutation
9.  A culturally adapted lifestyle intervention addressing a Middle Eastern immigrant population at risk of diabetes, the MEDIM (impact of Migration and Ethnicity on Diabetes In Malmö): study protocol for a randomized controlled trial 
Trials  2013;14:279.
Studies have shown that lifestyle interventions are effective in preventing or delaying the onset of type 2 diabetes in high-risk patients. However, research on the effectiveness of lifestyle interventions in high-risk immigrant populations with different cultural and socioeconomic backgrounds is scarce. The aim was to design a culturally adapted lifestyle intervention for an immigrant population and to evaluate its effectiveness and cost-effectiveness.
In this randomized controlled trial, 308 participants (born in Iraq, living in Malmö, Sweden and at high risk of type 2 diabetes) will be allocated to either a culturally adapted intervention or a control group. The intervention will consist of 10 group counseling sessions focusing on diet, physical activity and behavioral change over 6 months, and the offer of exercise sessions. Cultural adaptation includes gender-specific exercise sessions, and counseling by a health coach community member. The control group will receive the information about healthy lifestyle habits provided by the primary health care center. The primary outcome is change in fasting glucose level. Secondary outcomes are changes in body mass index, insulin sensitivity, physical activity, food habits and health-related quality of life. Measurements will be taken at baseline, after 3 and 6 months. Data will be analyzed by the intention-to-treat approach. The cost-effectiveness during the trial period and over the longer term will be assessed by simulation modeling from patient, health care and societal perspectives.
This study will provide a basis to measure the effectiveness of a lifestyle intervention designed for immigrants from the Middle East in terms of improvement in glucose metabolism, and will also assess its cost-effectiveness. Results from this trial may help health care providers and policy makers to adapt and implement lifestyle interventions suitable for this population group that can be conducted in the community.
Trial registration, NCT01420198
PMCID: PMC3844588  PMID: 24006857
10.  Low prevalence of irritable bowel syndrome in primary health care in four Swedish counties 
Few large-scale studies have examined the prevalence of irritable bowel syndrome (IBS) and the number of visits among IBS patients in a primary health care setting. The aim of this study was to assess the prevalence of IBS in primary health care in four Swedish counties. Another aim was to study the number of visits among the IBS patients.
A register-based study.
A primary health care database with information on patients from 71 primary health care centres in the Swedish counties of Stockholm, Uppsala, Värmland, and Gotland.
The primary health care database contains individual-level data for 919 954 patients for the period 2001–2007.
Main outcome measures
Prevalence of IBS diagnosis.
10 987 patients had a diagnosis of IBS, which corresponds to a prevalence of 1.2%. IBS was most common in the 25–44 years age group (37% of IBS patients); 71% of IBS patients were female, and 81% of IBS patients visited their GP six or more times, compared with 46% of non-IBS patients. However, 95% of the IBS patients visited their GP three times or fewer for IBS.
Conclusion and implications
The prevalence of IBS was low among Swedish primary health care patients. This might suggest that IBS patients are insufficiently diagnosed in Swedish primary health care.
PMCID: PMC3750433  PMID: 23906034
Epidemiology; gender; general practice; irritable bowel syndrome; prevalence; primary health care; Sweden
Most testicular germ cell tumors originate from carcinoma in situ cells in fetal life, possibly related to sex hormone imbalances in early pregnancy. Previous studies of association between gestational age at birth and testicular cancer have yielded discrepant results and have not examined extreme preterm birth. Our objective was to determine whether low gestational age at birth is independently associated with testicular cancer in later life. We conducted a national cohort study of 354,860 men born in Sweden in 1973–1979, including 19,214 born preterm (gestational age <37 weeks) of whom 1,279 were born extremely preterm (22–29 weeks), followed for testicular cancer incidence through 2008. A total of 767 testicular cancers (296 seminomas and 471 nonseminomatous germ cell tumors) were identified in 11.2 million person-years of follow-up. Extreme preterm birth was associated with an increased risk of testicular cancer (hazard ratio 3.95; 95% CI, 1.67–9.34) after adjusting for other perinatal factors, family history of testicular cancer, and cryptorchidism. Only five cases (three seminomas and two nonseminomas) occurred among men born extremely preterm, limiting the precision of risk estimates. No association was found between later preterm birth, post-term birth, or low or high fetal growth and testicular cancer. These findings suggest that extreme but not later preterm birth may be independently associated with testicular cancer in later life. They are based on a small number of cases and will need confirmation in other large cohorts. Elucidation of the key prenatal etiologic factors may potentially lead to preventive interventions in early life.
PMCID: PMC3349806  PMID: 22314417
gestational age; premature birth; nonseminomatous germ cell tumor; seminoma; testicular neoplasms
12.  Perinatal and Family Risk Factors for Non-Hodgkin Lymphoma in Early Life: A Swedish National Cohort Study 
The incidence of non-Hodgkin lymphoma (NHL) in early life has increased in recent decades, but the relevant risk factors remain largely unknown. We examined perinatal and family risk factors for NHL in childhood through young adulthood.
We conducted a national cohort study of 3 571 574 individuals born in Sweden in 1973–2008 who were followed for incidence of NHL through 2009 (ages 0–37 years). Detailed information on perinatal and family characteristics and NHL diagnoses were obtained from national birth and cancer registries. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between perinatal and family variables and NHL; P values are from two-sided tests.
There were 936 NHL case patients identified in 66.3 million person-years of follow-up. Independent risk factors for NHL included family history of NHL in either a sibling (adjusted HR = 9.84; 95% CI = 2.46 to 39.41; P = .001) or parent (adjusted HR = 2.36; 95% CI = 1.27 to 4.38; P = .007); high fetal growth (for ≥2 SDs relative to 0 to <1 SD from the mean: adjusted HR = 1.64; 95% CI = 1.19 to 2.25; P = .002); older maternal age (adjusted HR for each 5-year increment = 1.11; 95% CI = 1.04 to 1.19; P trend = .004); low birth order (adjusted HR for each increment of one birth = 0.91; 95% CI = 0.84 to 0.99; P trend = .02); and male sex (adjusted HR = 1.58; 95% CI = 1.38 to 1.80; P < .001). Male sex was associated with onset of NHL before 15 years of age but not with later-onset NHL, whereas the other risk factors did not vary by age at diagnosis. No association was found between gestational age at birth, twinning, paternal age, or parental education and NHL.
In this large national cohort study, family history of NHL, high fetal growth, older maternal age, low birth order, and male sex were independent risk factors for NHL in early life.
PMCID: PMC3732249  PMID: 22623506
13.  Do Reproductive Factors Influence T, N, and M Classes of Ductal and Lobular Breast Cancers? A Nation-Wide Follow-Up Study 
PLoS ONE  2013;8(5):e58867.
The clinical tumor-node-metastasis (T, N and M) classes of breast cancers provide important prognostic information. However, the possible association of TNM classes with reproductive factors has remained largely unexplored. Because every woman has a reproductive history, implications to outcome prediction are potentially significant.
During the study period from 2002 through 2008, 5,614 pre- and 27,310 postmenopausal patients were identified in the Swedish Family-Cancer Database. Ordinal logistic regression analysis was used to estimate odds ratios (ORs) for TNM classes of breast cancers by histology. The reproductive variables were parity, age at first and last childbirth and time interval between first and last childbirth.
Among postmenopausal patients, the ORs for high-T class (T2–T4) (tumor size ≥2 cm) and metastasis were decreased by parity. A late age at first and last childbirth associated with high-T class and the effects were higher for lobular (OR for late age at first childbirth  = 2.85) than ductal carcinoma. Overall, long time interval between first and last childbirth was related to high-T class and metastasis. However, a short time interval between first and last childbirth in patients with late age at first or last childbirth increased the risk of metastasis. Late age at last childbirth was associated with increased occurrence of lobular carcinoma in situ. Among premenopausal ductal carcinoma patients, nulliparity and early age at first childbirth were associated with high-T class.
Increasing parity was protective against high-T class and metastasis; late ages at first and last childbirth were risk factors for high-T class in postmenopausal breast cancers. The current decline in parity and delayed age at first childbirth in many countries may negatively influence prognosis of breast cancer.
PMCID: PMC3667089  PMID: 23734170
Annals of Epidemiology  2012;22(4):233-238.
Preterm birth is associated with gastric acid-related disorders in infancy, but no studies have examined this association beyond early childhood. We used antisecretory medication data to explore whether preterm birth is associated with gastric acid-related disorders in young adulthood.
National cohort study of 626,811 individuals born in Sweden in 1973–1979, followed up for antisecretory (proton pump inhibitor and H2-receptor antagonist) medication prescriptions from all outpatient and inpatient pharmacies nationwide in 2005–2009 (ages 25.5–37.0 years). We excluded individuals with congenital anomalies, and examined potential confounding by other comorbidities identified on the basis of oral anti-inflammatory or corticosteroid medication prescription.
Gestational age at birth was inversely associated with antisecretory medication prescription in young adulthood. Adjusted odds ratios for ≥1 antisecretory medication prescription/year were 3.38 (95% CI, 1.73–6.62) for individuals born at 22–27 weeks, 1.38 (95% CI, 1.19–1.60) for those born at 28–34 weeks, and 1.19 (95% CI, 1.06–1.32) for those born at 35–36 weeks, relative to those born full-term (37–42 weeks). Exclusion of individuals who were prescribed oral anti-inflammatory or corticosteroid medications (≥1/year) had little effect on these results.
These findings suggest that low gestational age at birth may be independently associated with an increased risk of gastric acid-related disorders in young adulthood.
PMCID: PMC3319267  PMID: 22382080
gastric acid; gastroesophageal reflux; gestational age; premature birth
15.  Within-Family Environmental Transmission of Drug Abuse 
JAMA psychiatry (Chicago, Ill.)  2013;70(2):235-242.
Drug abuse (DA) strongly runs in families. Does this result solely from genetic factors or does the family environment contribute?
To determine the familial environmental contribution to the risk for DA.
Follow-up in 9 public databases (1961–2009) in siblings and spouses.
A total of 137 199 sibling pairs and 7561 spousal pairs containing a proband with DA and matched control probands.
Main Outcome Measures
Drug abuse recorded in medical, legal, or pharmacy registry records.
In the best-fit model, which contained significant linear, quadratic, and cubic effects, among full sibling pairs containing a proband with DA, the relative risk for DA in the sibling declined from more than 6.0 for siblings born within 2 years of each other to less than 4.5 when born 10 years apart. Controlling for age differences in full sibling pairs, the hazard rate for DA in a sibling when the affected proband was older vs younger was 1.42 (95% CI, 1.31–1.54). In the best-fit model, which contained significant linear, quadratic, and cubic effects, among spousal pairs containing a proband with DA, the relative risk for DA in the spouse declined from more than 25.0 within 1 year of proband DA registration to 6.0 after 5 years.
Controlling for genetic effects by examining only full siblings, sibling resemblance for the risk for DA was significantly greater in pairs closer vs more distant in age. Older siblings more strongly transmitted the risk for DA to their younger siblings than vice versa. After one spouse is registered for DA, the other spouse has a large short-lived increase in DA risk. These results support strong familial environmental influences on DA at various life stages. A complete understanding of the familial transmission of DA will require knowledge of how genetic and familial environmental risk factors act and interact over development.
PMCID: PMC3609433  PMID: 23229904
16.  Neighbourhood Environment and Stroke: A Follow-Up Study in Sweden 
PLoS ONE  2013;8(2):e56680.
In recent years, research on the association between physical environments and cardiovascular disease outcomes has gained momentum with growing attention being paid to Geographic Information Systems (GIS). This nationwide study is the first to examine the effect of neighbourhood physical environments on individual-level stroke, using GIS-based measures of neighbourhood availability of potentially health-damaging (fast food restaurants and pubs/bars) and health-promoting (physical activity and healthcare) resources.
The study population comprised a nationwide sample of 2,115,974 men and 2,193,700 women aged 35–80 years who were followed between 1 December 2005 and 31 December 2007 in Sweden. Totally 42,270 first-ever strokes (both morbidity and mortality) were identified. Multilevel logistic regression models were used to estimate the association between neighbourhood availability of four different resources (fast food restaurants, pubs/bars, physical activity and healthcare) and individual-level stroke.
Principal Findings
There were significant associations between neighbourhood availability of the four types of neighbourhood resources and individual-level stroke. The significant odds ratios varied between 1.06 and 1.12 for men and 1.07 and 1.24 for women. After adjustment for age, income, and neighbourhood-level deprivation, the increased odds remained statistically significant for neighbourhood availability of fast food restaurants in both men and women.
Specific neighbourhood availability of resources were associated with individual-level stroke but most of these associations were explained by individual-level sociodemographic factors and neighbourhood-level deprivation.
PMCID: PMC3574004  PMID: 23457603
17.  High Familial Risk of Atrial Fibrillation/Atrial Flutter in Multiplex Families: A Nationwide Family Study in Sweden 
Although the heritability of atrial fibrillation/atrial flutter (AF/AFl) has been determined, the familial risk in multiplex families is unclear. The main aim of this nationwide study was to determine the familial risk of AF/AFl in multiplex families.
Methods and Results
We examined the familial risk of AF/AFl in the entire Swedish population. We linked Multigeneration Register data on individuals aged 0 to 76 years with Hospital Discharge Register data for 1987–2008 and Outpatient Register data for 2001–2008 to compare AF/AFl risk among relatives of all 300 586 individuals with AF/AFl with that among relatives of unaffected individuals. We used conditional logistic regression to investigate differences in exposure between cases and controls. Parents (odds ratio [OR] 1.95 [95% CI 1.89 to 2.00]) and siblings (OR=3.08 [3.00 to 3.16]) of cases had higher odds of AF/AFl than did parents and siblings of controls. AF/AFl ORs were increased in both sexes. For 2% of cases, both parents had AF/AFl, compared with only 0.7% of controls (OR=3.60 [3.30 to 3.92]). Moreover, 3% of cases had ≥2 siblings with AF/AFl, compared with 1% of controls (OR=5.72 [5.28 to 6.19]). In premature cases (diagnosed at age <50 years), the ORs were 5.04 (4.36 to 5.82) and 8.51 (6.49 to 11.15) for AF/AFl in both parents and AF/AFl in ≥2 siblings, respectively. The overall spouse OR was 1.16 (1.13 to 1.19).
Family history of AF/AFl increases the odds of AF/AFl in first‐degree relatives. High familial risks were observed in multiplex families.
PMCID: PMC3603261  PMID: 23525409
atrial fibrillation; atrial flutter; family history; risk factors; genetics
18.  Comparison of survival of patients with metastases from known versus unknown primaries: survival in metastatic cancer 
BMC Cancer  2013;13:36.
Cancer of unknown primary site (CUP) is considered an aggressive metastatic disease but whether the prognosis differs from metastatic cancers of known primary site is not known. Such data may give insight into the biology of CUP and the metastatic process in general.
6,745 cancer patients, with primary metastatic cancer at diagnosis, were identified from the Swedish Cancer Registry, and were compared with 2,881 patients with CUP. Patients were diagnosed and died between 2002 and 2008. The influence of the primary site, known or unknown, on survival in patients with metastases at specific locations was investigated. Hazard ratios (HRs) of death were estimated for several sites of metastasis, where patients with known primary sites were compared with CUP patients.
Overall, patients with metastatic cancers with known primary sites had decreased hazards of death compared to CUP patients (HR = 0.69 [95% CI = 0.66–0.72]). The exceptions were cancer of the pancreas (1.71 [1.54–1.90]), liver (1.58 [1.36–1.85]), and stomach (1.16 [1.02–1.31]). For individual metastatic sites, patients with liver or bone metastases of known origin had better survival than those with CUP of the liver and bone. Patients with liver metastases of pancreatic origin had an increased risk of death compared with patients with CUP of the liver (1.25 [1.06–1.46]). The median survival time of CUP patients was three months.
Patients with CUP have poorer survival than patients with known primaries, except those with brain and respiratory system metastases. Of CUP sites, liver metastases had the worst prognosis. Survival in CUP was comparable to that in metastatic lung cancer. The aggressive behavior of CUP may be due to initial immunosuppression and immunoediting which may allow accumulation of mutations. Upon escape from the suppressed state an unstoppable tumor spread ensues. These novel data on the epidemiology of the metastatic process at the population level demonstrated large survival differences in organ defined metastases depending on the original cancer.
PMCID: PMC3565900  PMID: 23356713
Metastasis; Cancer survival; Regression analysis; Cancer of unknown primary; CUP
19.  Genetic and Familial Environmental Influences on the Risk for Drug Abuse 
Archives of general psychiatry  2012;69(7):690-697.
Prior research suggests that drug abuse (DA) is strongly influenced by both genetic and familial environmental factors. No large-scale adoption study has previously attempted to verify and integrate these findings.
To determine how genetic and environmental factors contribute to the risk for DA.
Follow-up in 9 public databases (1961–2009) of adopted children and their biological and adoptive relatives.
The study included 18 115 adopted children born between 1950 and 1993; 78 079 biological parents and siblings; and 51 208 adoptive parents and siblings.
Main Outcome Measures
Drug abuse recorded in medical, legal, or pharmacy registry records.
Risk for DA was significantly elevated in the adopted offspring of biological parents with DA (odds ratio, 2.09; 95% CI, 1.66–2.62), in biological full and half siblings of adopted children with DA (odds ratio, 1.84; 95% CI, 1.28–2.64; and odds ratio, 1.41; 95% CI, 1.19–1.67, respectively), and in adoptive siblings of adopted children with DA (odds ratio, 1.95; 95% CI, 1.43–2.65). A genetic risk index (including biological parental or sibling history of DA, criminal activity, and psychiatric or alcohol problems) and an environmental risk index (including adoptive parental history of divorce, death, criminal activity, and alcohol problems, as well as an adoptive sibling history of DA and psychiatric or alcohol problems) both strongly predicted the risk for DA. Including both indices along with sex and age at adoption in a predictive model revealed a significant positive interaction between the genetic and environmental risk indices.
Drug abuse is an etiologically complex syndrome strongly influenced by a diverse set of genetic risk factors reflecting a specific liability to DA, by a vulnerability to other externalizing disorders, and by a range of environmental factors reflecting marital instability, as well as psychopathology and criminal behavior in the adoptive home. Adverse environmental effects on DA are more pathogenic in individuals with high levels of genetic risk. These results should be interpreted in the context of limitations of the diagnosis of DA from registries.
PMCID: PMC3556483  PMID: 22393206
Annals of epidemiology  2011;21(4):231-237.
Previous studies of neighborhood deprivation and mental disorders have yielded mixed results, possibly because they were based on different substrata of the population. We conducted a national multilevel study to determine whether neighborhood deprivation is independently associated with psychiatric medication prescription in a national population.
Nationwide outpatient and inpatient psychiatric medication data were analyzed for all Swedish adults (N=6,998,075) after 2.5 years of follow-up. Multilevel logistic regression was used to estimate the association between neighborhood deprivation (index of education, income, unemployment, and welfare assistance) and prescription of psychiatric medications (antipsychotics, antidepressants, anxiolytics, or hypnotics/sedatives), after adjusting for broadly measured individual-level sociodemographic characteristics.
For each psychiatric medication class, a monotonic trend of increasing prescription was observed by increasing level of neighborhood deprivation. The strongest associations were found for antipsychotics and anxiolytics, with adjusted odds ratios of 1.40 (95% CI, 1.36–1.44) and 1.24 (95% CI, 1.22–1.27), respectively, comparing the highest- to the lowest-deprivation neighborhood quintiles.
These findings suggest that neighborhood deprivation is associated with psychiatric medication prescription independent of individual-level sociodemographic characteristics. Further research is needed to elucidate the mechanisms by which neighborhood deprivation may affect mental health and to identify the most susceptible groups in the population.
PMCID: PMC3541429  PMID: 21376269
Anti-Anxiety Agents; Antidepressive Agents; Antipsychotic Agents; Hypnotics and Sedatives; Residence Characteristics
21.  Family history as a risk factor for recurrent hospitalization for lone atrial fibrillation: a nationwide family study in Sweden 
Although the heritability of atrial fibrillation (AF) has been determined, the relevance of family history of AF for the likelihood of recurrent hospitalization for AF is unknown. The aim of this nationwide study was to determine whether family history of AF is a risk factor of recurrent hospitalization for lone AF (LAF), i.e., AF with unknown etiology. The familial risk for first time LAF hospitalization was also determined and compared to the risk of recurrent hospitalization for LAF.
We examined whether family history of AF is a risk factor for recurrent hospitalization for LAF in the whole Swedish population. We linked Multigeneration Register data on individuals aged 0–60 years to Hospital Discharge Register data for the period 1987–2009 to compare LAF recurrent hospitalization risk among individuals with and without parental or sibling history of AF. We calculated hazard ratios (HRs) to determine the familial HR of recurrent hospitalization for LAF. Odds ratios (OR) were calculated for familial risk of first time LAF hospitalization.
The risk of recurrent LAF hospitalization was 1.23 (95% CI 1.17-1.30) for individuals with affected parents compared to 1.30 (95% CI 1.22-1.38) for those with affected siblings. After 10 years of follow up 50% of those without and 60% of those with family history had recurrent hospitalization for LAF. The risk of recurrent LAF hospitalization in individuals with two affected parents was 1.65 (95% CI 1.44-1.90). There was an interaction between age and family history, with family history having a weaker effect on LAF hospitalization risk in older age groups. The OR for first time LAF hospitalization was 2.08 (95% CI 2.02-2.15) for offspring with affected parents and 3.23 (95% CI 3.08-3.39) for individuals with affected siblings.
Family history of AF is a novel risk factor for recurrent LAF hospitalization. The higher recurrence hospitalization risk in multiplex families and younger individuals suggests a genetic contribution. However, the familial risk for recurrent LAF hospitalization was much lower than the risk for first time LAF hospitalization, suggesting that familial and possibly genetic factors are more important for first time LAF hospitalization than recurrent LAF hospitalization.
PMCID: PMC3523073  PMID: 23227964
Atrial fibrillation; Family history; Risk factors; Genetics
22.  Incidence and survival in non-hereditary amyloidosis in Sweden 
BMC Public Health  2012;12:974.
Amyloidosis is a heterogeneous disease caused by deposition of amyloid fibrils in organs and thereby interfering with physiological functions. Hardly any incidence data are available and most survival data are limited to specialist clinics.
Amyloidosis patients were identified from the Swedish Hospital Discharge and Outpatients Registers from years 2001 through 2008.
The incidence of non-hereditary amyloidosis in 949 patients was 8.29 per million person-years and the diagnostic age with the highest incidence was over 65 years. Secondary systemic amyloidosis showed an incidence of 1 per million and a female excess and the largest number of subsequent rheumatoid arthritis deaths; the median survival was 4 years. However, as rheumatoid arthritis deaths also occurred in other diagnostic subtypes, the incidence of secondary systemic amyloidosis was likely to be about 2.0 per million. The median survival of patients with organ-limited amyloidosis was 6 years. Most myeloma deaths occurred in patients diagnosed with unspecified or ‘other’ amyloidosis. These subtypes probably accounted for most of immunoglobulin light chain (AL) amyloidosis cases; the median survival time was 3 years.
The present diagnostic categorization cannot single out AL amyloidosis in the Swedish discharge data but, by extrapolation from myeloma cases, an incidence of 3.2 per million could be ascribed to AL amyloidosis. Similarly, based on rheumatoid arthritis death rates, an incidence of 2.0 could be ascribed to secondary systemic amyloidosis.
PMCID: PMC3503866  PMID: 23148499
23.  The association between perceived relationship discord at childbirth and parental postpartum depressive symptoms: a comparison of mothers and fathers in Sweden 
Upsala Journal of Medical Sciences  2012;117(4):430-438.
To examine whether mothers' and fathers' levels of perceived relationship discord at childbirth were associated with postpartum depressive symptoms when the child was 3 months old. Another aim was to examine parents' levels of self-reported depressive symptoms. The hypothesis was that parents with high levels of perceived relationship discord have higher levels of postpartum depressive symptoms than parents with low levels of perceived relationship discord.
One week after childbirth, 305 couples' perceived level of relationship discord was measured using the Dyadic Consensus Subscale (DCS) of the Dyadic Adjustment Scale (DAS). At 3 months postpartum, the same couples answered the Edinburgh Postnatal Depression Scale (EPDS) questionnaire. The relations between perceived level of relationship discord and postpartum depressive symptoms were analysed using standard non-parametric statistical methods.
The mothers and fathers partly differed regarding which areas of their relationship they perceived that they disagreed with their partners about. Furthermore, 16.5% of the mothers and 8.7% of the fathers reported postpartum depressive symptoms, and there was a moderate level of correlation between the DCS and EPDS scores.
These results may be useful for professionals in antenatal care and child health centres as well as for family caregivers who need to be aware that mothers and fathers may have different views on relationship discord and of the high level of depressive symptoms in recent parents. Further research is needed to examine perceived relationship discord and the development of depressive symptoms postpartum over a longer term.
PMCID: PMC3497219  PMID: 22574747
Depression postpartum; family; family relations; fathers; mothers
24.  Walkability parameters, active transportation and objective physical activity: moderating and mediating effects of motor vehicle ownership in a cross-sectional study 
Neighborhood walkability has been associated with physical activity in several studies. However, as environmental correlates of physical activity may be context specific, walkability parameters need to be investigated separately in various countries and contexts. Furthermore, the mechanisms by which walkability affects physical activity have been less investigated. Based on previous research, we hypothesized that vehicle ownership is a potential mediator. We investigated the associations between walkability parameters and physical activity, and the mediating and moderating effects of vehicle ownership on these associations in a large sample of Swedish adults.
Residential density, street connectivity and land use mix were assessed within polygon-based network buffers (using Geographic Information Systems) for 2,178 men and women. Time spent in moderate to vigorous physical activity was assessed by accelerometers, and walking and cycling for transportation were assessed by the International Physical Activity Questionnaire. Associations were examined by linear regression and adjusted for socio-demographic characteristics. The product of coefficients approach was used to investigate the mediating effect of vehicle ownership.
Residential density and land use mix, but not street connectivity, were significantly associated with time spent in moderate to vigorous physical activity and walking for transportation. Cycling for transportation was not associated with any of the walkability parameters. Vehicle ownership mediated a significant proportion of the association between the walkability parameters and physical activity outcomes. For residential density, vehicle ownership mediated 25% of the association with moderate to vigorous physical activity and 20% of the association with the amount of walking for transportation. For land use mix, the corresponding proportions were 34% and 14%. Vehicle ownership did not moderate any of the associations between the walkability parameters and physical activity outcomes.
Residential density and land use mix were associated with time spent in moderate to vigorous physical activity and walking for transportation. Vehicle ownership was a mediator but not a moderator of these associations. The present findings may be useful for policy makers and city planners when designing neighborhoods that promote physical activity.
PMCID: PMC3502165  PMID: 23035633
Accelerometer; Neighborhood walkability; Geographic information system; Mediator; Moderator
25.  Preterm birth and risk of epilepsy in Swedish adults 
Neurology  2011;77(14):1376-1382.
To determine whether preterm birth is associated with epilepsy in a national cohort of adults aged 25–37 years.
We conducted a national cohort study of 630,090 infants born in Sweden from 1973 through 1979, including 27,953 born preterm (<37 weeks), followed from 2005 to 2009 for 1) hospitalization for epilepsy and 2) outpatient and inpatient prescription of antiepileptic drugs. Epilepsy diagnoses and medication data were obtained from all hospitals and pharmacies throughout Sweden.
We found a strong association between preterm birth and epilepsy that increased by earlier gestational age. After adjusting for fetal growth and potential confounders, odds ratios for hospitalization for epilepsy were 4.98 (95%confidence interval [CI] 2.87–8.62) for those born at 23–31 weeks, 1.98 (95% CI 1.26–3.13) for those born at 32–34 weeks, and 1.76 (95% CI 1.30–2.38) for those born at 35–36 weeks, relative to those born full-term (37–42 weeks). A similar but slightly weaker trend was observed for the association between preterm birth and antiepileptic drug prescription. These associations persisted after excluding individuals with cerebral palsy, inflammatory diseases of the CNS, cerebrovascular disease, and brain tumors.
These findings suggest that preterm birth, including late preterm birth, is strongly associated with epilepsy in Swedish adults aged 25–37 years. This association was independent of fetal growth and was not mediated by cerebral palsy or other comorbidities.
PMCID: PMC3182754  PMID: 21968843

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