Swedish Case-control Study Research Articles

Physical Activity, Genetic Susceptibility, and the Risk of Latent Autoimmune Diabetes in Adults and Type 2 Diabetes.

PurposePhysical activity (PA) has been linked to a reduced risk of type 2 diabetes by reducing weight and improving insulin sensitivity. We investigated whether PA is associated with a lower incidence of latent autoimmune diabetes in adults (LADA) and whether the association is modified by genotypes of human leukocyte antigen (HLA), transcription factor 7-like 2 (TCF7L2)-rs7903146, or the fat mass and obesity-associated gene, FTO-rs9939609.MethodsWe combined data from a Swedish case-control study and a Norwegian prospective study including 621 incident cases of LADA and 3596 cases of type 2 diabetes. We estimated adjusted pooled relative risks (RRs) and 95% CI of diabetes in relation to high (≥ 30 minutes of moderate activity 3 times/week) self-reported leisure time PA, compared to sedentariness.ResultsHigh PA was associated with a reduced risk of LADA (RR 0.61; CI, 0.43-0.86), which was attenuated after adjustment for body mass index (BMI) (RR 0.90; CI, 0.63-1.29). The reduced risk applied only to noncarriers of HLA-DQB1 and -DRB1 (RR 0.49; CI, 0.33-0.72), TCF7L2 (RR 0.62; CI, 0.45-0.87), and FTO (RR 0.51; CI, 0.32-0.79) risk genotypes. Adjustment for BMI attenuated but did not eliminate these associations. For type 2 diabetes, there was an inverse association with PA (RR 0.49; CI, 0.42-0.56), irrespective of genotype.Main ConclusionsOur findings indicate that high PA is associated with a reduced risk of LADA in individuals without genetic susceptibility.

Antibiotic use and the development of inflammatory bowel disease: a national case-control study in Sweden

Use of antibiotics in early life has been linked with childhood inflammatory bowel disease (IBD), but data for adults are mixed, and based on smaller investigations that did not compare risk among siblings with shared genetic or environmental risk factors. We aimed to investigate the association between antibiotic therapy and IBD in a large, population-based study. In this prospective case-control study, we identified people living in Sweden aged 16 years or older, with a diagnosis of IBD based on histology and at least one diagnosis code for IBD or its subtypes (ulcerative colitis and Crohn's disease). We identified consecutive patients with incident IBD from the ESPRESSO (Epidemiology Strengthened by histoPathology Reports in Sweden) study, cross-referenced with the Swedish Patient Register and the Prescribed Drug Register. We accrued data for cumulative antibiotic dispensations until 1 year before time of matching for patients and up to five general population controls per patient (matched on the basis of age, sex, county, and calendar year). We also included unaffected full siblings as a secondary control group. Conditional logistic regression was used to estimate multivariable-adjusted odds ratios (aORs) and 95% CIs for diagnosis of incident IBD. We identified 23 982 new patients with IBD (15 951 ulcerative colitis, 7898 Crohn's disease, 133 unclassified IBD) diagnosed between Jan 1, 2007, and Dec 31, 2016. 117 827 matched controls and 28 732 siblings were also identified. After adjusting for several risk factors, aOR in patients who had used antibiotics versus those who had never used antibiotics was 1·88 (95% CI 1·79-1·98) for diagnosis of incident IBD, 1·74 (1·64-1·85) for ulcerative colitis, and 2·27 (2·06-2·49) for Crohn's disease. aOR was higher in patients who had received one antibiotic dispensation (1·11, 1·07-1·15), two antibiotic dispensations (1·38, 1·32-1·44), and three or more antibiotic dispensations (1·55, 1·49-1·61) than patients who had none. Increased risk was noted for ulcerative colitis (aOR with three or more antibiotic dispensations 1·47, 95% CI 1·40-1·54) and Crohn's disease (1·64, 1·53-1·76) with higher estimates corresponding to broad-spectrum antibiotics. Similar but attenuated results were observed when siblings were used as the reference group, with an aOR of 1·35 (95% CI 1·28-1·43) for patients who had received three or more dispensations, compared with general population controls. Higher cumulative exposure to systemic antibiotic therapy, particularly treatments with greater spectrum of microbial coverage, may be associated with a greater risk of new-onset IBD and its subtypes. The association between antimicrobial treatment and IBD did not appear to differ when predisposed siblings were used as the reference controls. Our findings, if substantiated by longer-term prospective studies in humans or mechanistic preclinical investigations, suggest the need to further emphasise antibiotic stewardship to prevent the rise in dysbiosis-related chronic diseases, including IBD. National Institutes of Health. Crohn's and Colitis Foundation.

Antibiotic Use Associated With Risk of Colorectal Polyps in a Nationwide Study

Use of antibiotics affects the composition of the microbiome and might affect development of colorectal polyps, which are precursors to colorectal cancer. We performed a nested case-control study in Sweden of 45,744 patients with a colorectal polyp (cases) in the nationwide gastrointestinal ESPRESSO histopathology cohort, using unaffected full siblings as controls (n= 93,307). Polyps were classified by morphology SnoMed codes into conventional adenomas and serrated polyps. Through linkage to the Prescribed Drug Register, we assessed use and cumulative dispensations of antibiotic until 1 year prior to polyp diagnosis for cases and their sibling controls. During a median study period of 6.9 years, compared with non-users, users of antibiotics (including 28,884 cases [63.1%] and 53,222 sibling controls [57.0%]) had a higher risk of colorectal polyps (odds ratio [OR], 1.08; 95% CI, 1.04-1.13). Risk increased with higher number of dispensations (OR for ≥ 6 dispensations, 1.33; 95% CI, 1.25-1.43) (Ptrend < .0001). We observed a stronger association with polyps for broad-spectrum antibiotics (OR comparing users to non-users, 1.23; 95% CI, 1.18-1.29) than for narrow-spectrum antibiotics (OR, 1.05; 95% CI, 1.01-1.10), and for tetracyclines and quinolones (OR, 1.21) than penicillin and other classes (ORs ranged from 1.04 to 1.16). The findings remained robust with several sensitivity analyses, including use of a 2-year lead-in period for antibiotic assessment and correction for misclassification in controls. Use of broad-spectrum antibiotics was more strongly associated with risk of serrated polyps (OR, 1.29; 95% CI, 1.21-1.38) compared with risk of conventional adenomas (OR, 1.17; 95% CI, 1.11-1.24). We found no differences in risk of colon vs rectal polyps with antibiotic use (Pheterogeneity > .10). We found stronger associations for younger (<50 years) vs older adults (≥50 years) for users of quinolones, sulfonamides, trimethoprim, and cephalosporins (Pinteraction < .001). In a nationwide case-control study in Sweden, after accounting for hereditary and early life environmental factors, antibiotic use was associated with increased risk of colorectal polyps. Our findings indicate a role for intestinal dysbiosis in early stages of colorectal carcinogenesis.

Methotrexate treatment for patients with psoriasis and risk of cutaneous melanoma: a nested case-control study.

Cutaneous malignant melanoma (CMM) is a highly immunogenic tumour. Patients with an impaired immune system have an enhanced risk for CMM and a worse prognosis. Methotrexate (MTX) is an anti-inflammatory and immunosuppressive drug frequently used to treat patients with psoriasis. An association between MTX and risk of CMM has previously been demonstrated in patients with rheumatoid arthritis. To investigate whether MTX increases the risk of CMM among patients with psoriasis. A nested case-control investigation from a Swedish cohort of patients with psoriasis was conducted. Data were obtained from available Swedish registers and included 395 patients with psoriasis who had previously been cancer-free and had a first CMM in the time period from 1 January 2010 to 31 December 2016. A total of 10 randomly selected cancer-free patients with psoriasis were matched per case with respect to age (same birth year) and sex. The accumulated MTX doses in both groups were obtained. Crude odds ratios (ORs) for the proportion of MTX in the respective group were calculated using conditional logistic regression analyses. Of 395 patients with psoriasis who had CMM, 97 (25%) had filled a prescription of MTX; of 3950 controls, the corresponding number was 954 (24%). In a conditional logistic regression analysis, no association between MTX exposure (ever use) and risk for CMM was observed (OR 1·0, 95% confidence interval 0·8-1·3). Moreover, no indication of a dose-response association was observed. In this Swedish nested case-control study, the use of MTX was not associated with an enhanced risk for CMM. These findings are reassuring for dermatologists in everyday clinical practice. What is already known about this topic? Methotrexate (MTX) treatment has been linked to an increased risk for cutaneous malignant melanoma (CMM) in an Australian cohort of patients with rheumatoid arthritis. In a previous retrospective Swedish cohort investigation, patients who had exclusively been prescribed MTX by a dermatologist did not have an enhanced risk for CMM compared with MTX-unexposed individuals. Nevertheless, this cohort did not specifically include patients with psoriasis. What does this study add? This Swedish nested case-control investigation included 395 previously cancer-free patients with psoriasis who had CMM (cases) and 3950 matched cancer-free patients with psoriasis (controls). No association between MTX exposure and risk for CMM in patients with psoriasis was observed. The results are reassuring for dermatologists using MTX to treat patients with psoriasis. Linked Comment: Haugaard and Egeberg. Br J Dermatol 2020; 183:608-609.

Clinical risk factors in SUDEP: A nationwide population-based case-control study.

ObjectiveWe conducted a nationwide case-control study in Sweden to test the hypothesis that specific clinical characteristics are associated with increased risk of sudden unexpected death in epilepsy (SUDEP).MethodsThe study included 255 SUDEP cases (definite and probable) and 1,148 matched controls. Clinical information was obtained from medical records and the National Patient Register. The association between SUDEP and potential risk factors was assessed by odds ratios (ORs) and 95% confidence intervals (CIs) and interaction assessed by attributable proportion due to interaction (AP).ResultsExperiencing generalized tonic-clonic seizures (GTCS) during the preceding year was associated with a 27-fold increased risk (OR 26.81, 95% CI 14.86–48.38), whereas no excess risk was seen in those with exclusively non-GTCS seizures (OR 1.15, 95% CI 0.54–48.38). The presence of nocturnal GTCS during the last year of observation was associated with a 15-fold risk (OR 15.31, 95% CI 9.57–24.47). Living alone was associated with a 5-fold increased risk of SUDEP (OR 5.01, 95% CI 2.93–8.57) and interaction analysis showed that the combination of not sharing a bedroom and having GTCS conferred an OR of 67.10 (95% CI 29.66–151.88), with AP estimated at 0.69 (CI 0.53–0.85). Among comorbid diseases, a previous diagnosis of substance abuse or alcohol dependence was associated with excess risk of SUDEP.ConclusionsIndividuals with GTCS who sleep alone have a dramatically increased SUDEP risk. Our results indicate that 69% of SUDEP cases in patients who have GTCS and live alone could be prevented if the patients were not unattended at night or were free from GTCS.

Environmental (Lifestyle) Risk Factors for LADA.

In order to prevent diabetes it is important to identify common, modifiable risk factors in the population. Such knowledge is extensive for type 2 diabetes but limited for autoimmune forms of diabetes. This review aims at summarizing the limited literature on potential environmental (lifestyle) risk factors for LADA. A PubMed search identified 15 papers estimating the risk of LADA in relation to lifestyle. These were based on data from two population-based studies; one Swedish case-control study and one Norwegian cohort study. Studies published to date indicate that the risk of LADA is associated with factors promoting insulin resistance and type 2 diabetes such as overweight, physical inactivity, smoking, low birth weight, sweetened beverage intake and moderate alcohol consumption (protective). Findings also indicate potential effects on autoimmunity exerted by intake of coffee (harmful) and fatty fish (protective). This supports the concept of LADA as being a hybrid form of diabetes with an etiology including factors associated with both insulin resistance and autoimmunity. LADA may in part be preventable through the same lifestyle modifications as type 2 diabetes including weight loss, physical activity and smoking cessation. However, current knowledge is hampered by the small number of studies and the fact that they exclusively are based on Scandinavian populations. There is a great need for additional studies exploring the role of lifestyle factors in the development of LADA.

Involvement of CGRP receptor RAMP1 in cluster headache: A Swedish case-control study

Background: Increased levels of the potent vasodilator calcitonin gene-related peptide (CGRP) have been found in ipsilateral jugular vein blood during the active phase of cluster headache (CH) and this is hypothesized to cause distinctive vasodilation. The receptor activity-modifying protein 1 (RAMP1) is part of the CGRP receptor complex responsible for ligand binding and specificity and therefore constitutes a promising candidate gene for CH. The aim of this study was to investigate the possible genetic association of RAMP1 with CH in Sweden, with focus on two RAMP1 single nucleotide polymorphisms, rs3754701 and rs7590387, and quantify RAMP1 mRNA expression levels in biological tissue from CH patients and controls. Methods: rs3754701 and rs7590387 were genotyped by quantitative polymerase chain reaction (qPCR) in 542 CH patients and 585 control subjects. RAMP1 mRNA expression was determined by reverse transcription qPCR in tissue from 12 CH patients and 12 controls. Results: We identified a significant difference between the CH patient and control groups for rs3754701 ( p = 0.0088). In addition, RAMP1 mRNA expression was enhanced in primary fibroblasts from CH patients compared to controls ( p = 0.0073). Conclusion: The association between rs3754701 and CH and the enhanced RAMP1 mRNA expression in CH patients support the hypothesis that CGRP and its receptor component RAMP1 are involved in CH pathophysiology.

Socioeconomic disparities associated with 29 common infectious diseases in Sweden, 2005–14: an individually matched case-control study

Although the association between low socioeconomic status and non-communicable diseases is well established, the effect of socioeconomic factors on many infectious diseases is less clear, particularly in high-income countries. We examined the associations between socioeconomic characteristics and 29 infections in Sweden. We did an individually matched case-control study in Sweden. We defined a case as a person aged 18-65 years who was notified with one of 29 infections between 2005 and 2014, in Sweden. Cases were individually matched with respect to sex, age, and county of residence with five randomly selected controls. We extracted the data on the 29 infectious diseases from the electronic national register of notified infections and infectious diseases (SmiNet). We extracted information on country of birth, educational and employment status, and income of cases and controls from Statistics Sweden's population registers. We calculated adjusted matched odds ratios (amOR) using conditional logistic regression to examine the association between infections or groups of infections and place of birth, education, employment, and income. We included 173 729 cases notified between Jan 1, 2005, and Dec 31, 2014 and 868 645 controls. Patients with invasive bacterial diseases, blood-borne infectious diseases, tuberculosis, and antibiotic-resistant infections were more likely to be unemployed (amOR 1·59, 95% CI 1·49-1·70; amOR 3·62, 3·48-3·76; amOR 1·88, 1·65-2·14; and amOR 1·73, 1·67-1·79, respectively), to have a lower educational attainment (amOR 1·24, 1·15-1·34; amOR 3·63, 3·45-3·81; amOR 2·14, 1·85-2·47; and amOR 1·07, 1·03-1·12, respectively), and to have a lowest income (amOR 1·52, 1·39-1·66; amOR 3·64, 3·41-3·89; amOR 3·17, 2·49-4·04; and amOR 1·2, 1·14-1·25, respectively). By contrast, patients with food-borne and water-borne infections were less likely than controls to be unemployed (amOR 0·74, 95% CI 0·72-0·76), to have lower education (amOR 0·75, 0·73-0·77), and lowest income (amOR 0·59, 0·58-0·61). These findings indicate persistent socioeconomic inequalities in infectious diseases in an egalitarian high-income country with universal health care. We recommend using these findings to identify priority interventions and as a baseline to monitor programmes addressing socioeconomic inequalities in health. The Public Health Agency of Sweden.

Implications for the migraine SNP rs1835740 in a Swedish cluster headache population

BackgroundCluster headache is a severe headache disorder with unknown aetiology. The pathophysiology and symptoms present certain common features with migraine. Specifically, activation of the trigeminal vascular system seems to be involved in both disorders, which is hypothesized to result in neurogenic inflammation and vasodilation of the cerebral vessels. In addition, genetic factors have been implicated in both migraine and cluster headache.ObjectiveIn order to determine whether or not migraine and cluster headache share genetic risk factors, we screened two genetic variants known to increase the risk of migraine in Sweden in a Swedish cluster headache case-control study population.MethodsIn all, 541 patients and 581 control subjects were genotyped for rs1835740 in close proximity to MTDH (metadherin) and rs2651899 in the PRDM16 (PR/SET domain 16) gene, using TaqMan® real-time PCR and pyrosequencing. In addition, we analyzed MTDH gene expression in a subset of the material, using reverse transcription real-time PCR to determine relative mRNA levels in primary fibroblast cell lines from patients and controls.ResultsWe found a trend for association between rs1835740, which is reported to affect MTDH mRNA levels, and cluster headache in our Swedish case-control material (p = 0.043, Χ2 = 4.102). This association was stronger in a subgroup of patients suffering from both cluster headache and migraine (p = 0.031, Χ2 = 6.964). We could further confirm that rs1835740 has an effect on the transcriptional activity of MTDH. In this Swedish cluster headache cohort we did not find an association with the rs2651899 variant.ConclusionsWe conclude that rs1835740 is a potential risk factor for cluster headache in Sweden. Our data indicates that rs1835740 and MTDH might be involved in neurovascular headaches in general whilst rs2651899 is specifically related to migraine.

Gastrointestinal Infection Increases Odds of Inflammatory Bowel Disease in a Nationwide Case–Control Study

Gastrointestinal infections have been associated with later development of inflammatory bowel diseases (IBD). However, studies have produced conflicting results. We performed a nationwide case-control study in Sweden to determine whether gastroenteritis is associated with the development of Crohn's disease (CD) or ulcerative colitis (UC). Using the Swedish National Patient Register, we identified 44,214 patients with IBD (26,450 with UC; 13,387 with CD; and 4377 with IBD-unclassified) from 2002 to 2014 and matched them with 436,507 individuals in the general population (control subjects). We then identified patients and control subjects with reported episodes of gastroenteritis (from 1964 to 2014) and type of pathogen associated. We collected medical and demographic data and used logistic regression to estimate odds ratios (ORs) for IBD associated with enteric infection. Of the patients with IBD, 3105 (7.0%) (1672 with UC, 1050 with CD, and 383 with IBD-unclassified) had a record of previous gastroenteritis compared with 17,685 control subjects (4.1%). IBD cases had higher odds for an antecedent episode of gastrointestinal infection (aOR, 1.64; 1.57-1.71), bacterial gastrointestinal infection (aOR, 2.02; 1.82-2.24), parasitic gastrointestinal infection (aOR, 1.55; 1.03-2.33), and viral gastrointestinal infection (aOR, 1.55; 1.34-1.79). Patients with UC had higher odds of previous infection with Salmonella, Escherichia coli, Campylobacter, or Clostridium difficile compared to control subjects. Patients with CD had higher odds of previous infection with Salmonella, Campylobacter, Yersinia enterocolitica, Cdifficile, amoeba, or norovirus compared to control subjects. Increasing numbers of gastroenteritis episodes were associated with increased odds of IBD, and a previous episode of gastroenteritis remained associated with odds for IBD more than 10 years later (aOR, 1.26; 1.19-1.33). In an analysis of the Swedish National Patient Register, we found previous episodes of gastroenteritis to increase odds of later development of IBD. Although we cannot formally exclude misclassification bias, enteric infections might induce microbial dysbiosis that contributes to the development of IBD in susceptible individuals.

Wild and domestic bird faeces likely source of psittacosis transmission-A case-control study in Sweden, 2014-2016.

Psittacosis is a zoonotic disease transmitted by birds. In Sweden, where psittacosis is notifiable, an average of eight cases per year were reported between 2002 and 2012. In 2013, an unusual increase in cases in southern Sweden was associated with exposure to wild birds. To further explore specific risk factors connected to wild birds and identify other risk factors for sporadic psittacosis, we conducted a case-control study including all domestically acquired psittacosis cases reported between December 2014 and April 2016 in Sweden. Cases were age-, sex- and geo-matched to controls randomly selected from a population register. Cases and controls completed a questionnaire investigating detailed exposures to wild and domestic birds. We compared cases to controls, calculating adjusted matched odds ratios (amOR) using conditional logistic regression. Thirty-one cases were notified: all cases lived in southern Sweden and 26 were ill during winter season. Two risk factors were independently associated with psittacosis infection: cleaning a wild bird feeder (amOR=18.95; 95% CI: 2.11-170.03) and owning domestic birds (amOR=5.55, 95% CI: 1.16-26.61). Our results suggest that exposure to bird faeces, for example when cleaning a wild bird feeder, was the main route of transmission. Following this study, the Public Health Agency of Sweden published recommendations on good practices when cleaning surfaces contaminated with bird faeces and recommended use of bird feeders with a design limiting faeces accumulation.

Deep breast pain during lactation: a case-control study in Sweden investigating the role of Candida albicans

BackgroundDeep breast pain during lactation, with or without accompanying nipple pain and soreness continues to be anecdotally linked to infection by Candia albicans despite lack of robust evidence in the literature that Candida albicans is the cause of women’s breast symptoms.MethodsA case-control study of breastfeeding women in Sweden with (n 35) and without (n 35) symptoms that may be attributable to Candida albicans was carried out. The symptoms were radiating, burning and penetrating or non-penetrating breast pain with or without associated nipple pain during or after breastfeeding. The primary aim of the study was to test the hypothesis that breastfeeding women with symptoms commonly associated with Candida albicans infection will have a growth of Candida albicans in their breast milk significantly more often than women without these symptoms. A secondary aim was comparison of breastfeeding self-efficacy, measured by the BSES-SF (Breastfeeding Self Efficacy Scale –Short Form), between cases and controls.ResultsNone of the women in the control group and eight of the women in the case group showed a growth of Candida albicans in their breast milk (p < 0.01), which confirms the hypothesis. There were no statistically significant differences in severity or type of symptoms between those in the case group with and without growth of Candida albicans in their breast milk. Results of the BSES-SF measurement showed no statistically significant differences between cases and controls. However, when analyses were stratified for parity, multiparous controls showed statistically significant higher scores for breastfeeding self-efficacy than multiparous cases.ConclusionsNeither clinical symptoms nor microbial cultivation appear to be reliable means for making a diagnosis of Candida albicans infection of the breast. Skilled breastfeeding consultants should offer support and help with positioning, attachment and identification of physical impediments to successful breastfeeding. Professionals should be aware that it is possible that uncertainty in the breastfeeding situation may to some extent account for mothers’ breast symptoms. The ISRCTN (International Standard Randomised Controlled Trial Number) identity for this case-control study is ISRCTN88839993. The study was retrospectively registered on 30 November 2016.

Overweight, obesity and the risk of LADA: results from a Swedish case\u2013control study and the Norwegian HUNT Study

Aims/hypothesisExcessive weight is a risk factor for type 2 diabetes, but its role in the promotion of autoimmune diabetes is not clear. We investigated the risk of latent autoimmune diabetes in adults (LADA) in relation to overweight/obesity in two large population-based studies.MethodsAnalyses were based on incident cases of LADA (n = 425) and type 2 diabetes (n = 1420), and 1704 randomly selected control participants from a Swedish case–control study and prospective data from the Norwegian HUNT Study including 147 people with LADA and 1,012,957 person-years of follow-up (1984–2008). We present adjusted ORs and HRs with 95% CI.ResultsIn the Swedish data, obesity was associated with an increased risk of LADA (OR 2.93, 95% CI 2.17, 3.97), which was even stronger for type 2 diabetes (OR 18.88, 95% CI 14.29, 24.94). The association was stronger in LADA with low GAD antibody (GADA; <median) (OR 4.25; 95% CI 2.76, 6.52) but present also in LADA with high GADA (OR 2.14; 95% CI 1.42, 3.24). In the Swedish data, obese vs normal weight LADA patients had lower GADA levels, better beta cell function, and were more likely to have low-risk HLA-genotypes. The combination of overweight and family history of diabetes (FHD) conferred an OR of 4.57 (95% CI 3.27, 6.39) for LADA and 24.51 (95% CI 17.82, 33.71) for type 2 diabetes. Prospective data from HUNT indicated even stronger associations; HR for LADA was 6.07 (95% CI 3.76, 9.78) for obesity and 7.45 (95% CI 4.02, 13.82) for overweight and FHD.Conclusions/interpretationOverweight/obesity is associated with increased risk of LADA, particularly when in combination with FHD. These findings support the hypothesis that, even in the presence of autoimmunity, factors linked to insulin resistance, such as excessive weight, could promote onset of diabetes.

Perceived Physical Strain at Work and Incidence of Prostate Cancer – a Case-Control Study in Sweden and Finland

The evidence that prostate cancer is associated to physical inactivity is inconsistent. We studied the association of perceived physical workload (PPWL) at work and incidence of prostate cancer in a case-control setting. We used data from the Nordic Occupational Cancer study from Finland and Sweden. Five population controls were selected for each prostate cancer patient, matched on age and country. We had 239,835 cases and 1,199,175 controls in our study. For each case and control we estimated cumulative PPWL based on probability, level and duration of PPWL using the NOCCA Job Exposure Matrix. We then stratified individuals as having no exposure (reference category), low physical activity (below 50th percentile of the exposed), moderate exposure (50th-90th percentile) and high exposure (90th percentile and higher). The hazard ratios for prostate cancer from the lowest to highest cumulative PPWL levels were 0.90 (95% confidence interval 0.89-0.91), 0.88 (0.87-0.89) and 0.93 (0.92-0.95). There was no statistically significant dose response effect of PPWL on prostate cancer incidence. Inclusion of socioeconomic status in the model did not substantially change the result. The results were similar before Prostate Specific Antigen (PSA) testing and during the years of PSA testing in these countries. In summary, individuals with physical strain at work had a lower risk of invasive prostate cancer as compared to individuals without physical strain at work.

Building and validating a prediction model for paediatric type 1 diabetes risk using next generation targeted sequencing of class II HLA genes.

It is of interest to predict possible lifetime risk of type 1 diabetes (T1D) in young children for recruiting high-risk subjects into longitudinal studies of effective prevention strategies. Utilizing a case-control study in Sweden, we applied a recently developed next generation targeted sequencing technology to genotype class II genes and applied an object-oriented regression to build and validate a prediction model for T1D. In the training set, estimated risk scores were significantly different between patients and controls (P=8.12×10-92 ), and the area under the curve (AUC) from the receiver operating characteristic (ROC) analysis was 0.917. Using the validation data set, we validated the result with AUC of 0.886. Combining both training and validation data resulted in a predictive model with AUC of 0.903. Further, we performed a "biological validation" by correlating risk scores with 6 islet autoantibodies, and found that the risk score was significantly correlated with IA-2A (Z-score=3.628, P<0.001). When applying this prediction model to the Swedish population, where the lifetime T1D risk ranges from 0.5% to 2%, we anticipate identifying approximately 20 000 high-risk subjects after testing all newborns, and this calculation would identify approximately 80% of all patients expected to develop T1D in their lifetime. Through both empirical and biological validation, we have established a prediction model for estimating lifetime T1D risk, using class II HLA. This prediction model should prove useful for future investigations to identify high-risk subjects for prevention research in high-risk populations.

An efficient sampling strategy for selection of biobank samples using risk scores

The aim of this study was to suggest a new sample-selection strategy based on risk scores in case-control studies with biobank data. An ongoing Swedish case-control study on fetal exposure to endocrine disruptors and overweight in early childhood was used as the empirical example. Cases were defined as children with a body mass index (BMI) ⩾18 kg/m2 ( n=545) at four years of age, and controls as children with a BMI of ⩽17 kg/m2 ( n=4472 available). The risk of being overweight was modelled using logistic regression based on available covariates from the health examination and prior to selecting samples from the biobank. A risk score was estimated for each child and categorised as low (0-5%), medium (6-13%) or high (⩾14%) risk of being overweight. The final risk-score model, with smoking during pregnancy ( p=0.001), birth weight ( p<0.001), BMI of both parents ( p<0.001 for both), type of residence ( p=0.04) and economic situation ( p=0.12), yielded an area under the receiver operating characteristic curve of 67% ( n=3945 with complete data). The case group ( n=416) had the following risk-score profile: low (12%), medium (46%) and high risk (43%). Twice as many controls were selected from each risk group, with further matching on sex. Computer simulations showed that the proposed selection strategy with stratification on risk scores yielded consistent improvements in statistical precision. Using risk scores based on available survey or register data as a basis for sample selection may improve possibilities to study heterogeneity of exposure effects in biobank-based studies.

Tissue trauma and the subsequent risk of soft tissue sarcoma of the extremity: A population based case-control study in Sweden.

e13088 Background: Soft tissue sarcomas (STS) are a rare group of heterogeneous tumors that may occur in the extremities. Little is known of their etiologies and only a handful putative risk factors have been identified. Studies as well as case reports have connected soft tissue tumors to events of physical trauma. There is mounting evidence of inflammation as both an initiator and promotor of tumorigenesis, as well progression. Moreover, as the physiological response of tissue repair and regeneration is mediated through inflammation, it is not unlikely that physical injury may cause and/or contribute to tumor initiation, promotion and/or progression, not least when the subsequent inflammation becomes chronic. Methods: We conducted a matched case control study in a total population in the South of Sweden 1988-2009, collecting 249 cases to examine the risk of STS of the extremities (STSE) following exposure to physical trauma such as accidental injury and/or surgery. Results: Having been exposed to surgery or injury from accidents to any part of the body both increased the risk of STSE, OR 2.1 (1.5 – 3) and 1.5 (1.1 – 2.1), respectively. Adjusting for potential confounders yielded ORs of 2.4 (1.6 – 3.6) and 1.4 (1.00 – 2.00). Surgery related odds ratios (SOR) varied with STSE histological subtype, from 1.2 to 4.2. UPS/MFH, Leiomyosarcoma and Liposarcoma showed significantly elevated SORs that were significantly greater than for remaining subtypes (P = 0.029). The accident related odds ratio (AOR) varied from 0.8 to 3.5, being significantly elevated for Leiomyo- and Liposarcoma, and the AOR of the two combined was significantly greater than remaining subtypes (P = 0.045). Analyzing surgery or accidental injury to a given part of the body and the subsequent STSE risk in the same location showed the SOR to be 4.13 (1.87 – 9.15) and the AOR was 2.29 (1.21 – 4.32). Conclusions: The population attributable risk of having had surgery was 37% (20 – 53%) and accidental injury was 13% (2 – 24%). Combined, the PAR was 43% (25 – 57%), indicating that tissue trauma may be an important contributing factor in sarcomagenesis of the extremities.

Maternal hirsutism and autism spectrum disorders in offspring.

Because animal and human studies indicate that androgen exposure can influence neurodevelopment, it has been hypothesized that prenatal exposure to excess androgens may predispose to disorders with male-skewed ratio such as autism spectrum disorders (ASD). Therefore, maternal conditions characterized by hyperandrogenism such as polycystic ovary syndrome (PCOS) or hirsutism may be relevant to child ASD. We previously found in a large Swedish case-control study of 23,748 ASD cases and 208,796 matched controls that PCOS in mothers is associated with increased offspring risk of ASD. In the same sample, we have now examined whether maternal diagnoses of hirsutism were associated with ASD. In both unadjusted logistic regression models and models adjusted for a variety of covariates, hirsutism was associated with higher odds of ASD. The most adjusted odds ratios for associations with ASD for hirsutism diagnosis before birth and lifetime diagnosis of hirsutism were 1.64 (95% CI: 0.94, 2.83) and 1.26 (95% CI: 1.01, 1.57), respectively. The presence of an association of maternal hirsutism with child ASD is consistent with the hypothesis that androgens may be involved in the etiology of ASD. Autism Res 2017, 10: 1544-1546. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

Primary Upper Extremity Deep Venous Thrombosis and Comorbidity: A Population-Based Nationwide Study in Sweden

Abstract BackgroundThere have been few studies on primary upper extremity deep vein thrombosis (UEDVT) and the comorbidity is not very well known, in contrast to secondary UEDVT.MethodsWe conducted a nationwide, population-based case control study in Sweden using data from the Swedish National Patient Register (NPR).We examined comorbidity in 25 cases with a confirmed UEDVT with a control group (appendicitis) during the years 2001–2011 in patients over 18 years old. We defined comorbidity as the number of unique ICD codes (International Statistical Classification of Diseases and Related Health Problems) and the total number of healthcare contacts.ResultsThe number of unique ICD codes was similar between cases and controls, although they differed regarding specific diagnoses. Patients with a UEDVT were more likely to later have a diagnosis related to blood-forming organs, the endocrine system, the nervous system, the circulatory system, and to the skin and musculoskeletal systems, compared with the controls.Diagnoses for symptoms from the brachial plexus and diagnoses referring to pain and discomfort of the upper extremity were more frequent in the cases. The major difference occurred in diagnoses involving the circulatory system, which were more frequent in the cases. The most important cases and controls were similar regarding diagnoses of malignancy. The cases had a significantly higher number of healthcare contacts.ConclusionThe type of comorbidity and the number of healthcare contacts differed between patients with a diagnosis of UEDVT, compared with those with appendicitis. There was no difference regarding malignancies, which implies that primary UEDVT is a benign disorder.

Symptoms of depression and their relation to myocardial infarction and periodontitis.

Psychosocial stress and depression are established risk factors for cardiovascular disease and a relationship to periodontitis has been suggested. We studied symptoms of depression and their relation to myocardial infarction and periodontitis. In a Swedish case-control study, 805 patients, <75 years with a first myocardial infarction and 805 controls without myocardial infarction were matched for age, gender and geographic area. Mean age was 62±8 years and 81% were male. Standardised physical examination and dental panoramic X-ray for grading of periodontal status was performed. Medical history including risk factors related to cardiovascular disease and periodontitis was collected as was detailed information on perceived stress at home and work, and symptoms of depression (Montgomery Åsberg Depression Scale). A Montgomery Åsberg Depression Scale score ⩾13 was considered clinically relevant. A family history of cardiovascular disease, smoking and divorce was more frequent among patients than controls. Patients had more symptoms of depression than controls (14 vs 7%; p<0.001) but received less anti-depressive treatment (16 vs 42%; p<0.001). Symptoms of depression doubled the risk for myocardial infarction (Montgomery Åsberg Depression Scale: odds ratio 2.17 (95% confidence interval 1.41-3.34)). There was no difference in symptoms of depression between study participants with and without periodontitis. Patients with a first myocardial infarction were more frequently depressed than matched controls without myocardial infarction, but received less anti-depressive treatment. A relationship between depression and periodontitis could not be confirmed.