Metabolic dysfunction-associated steatotic liver disease has become the most common cause of hepatocellular carcinoma in Sweden: A nationwide cohort study.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease globally, and can lead to hepatocellular carcinoma (HCC), a leading cause of cancer-related death. We aimed to determine the extent to which MASLD is an increasing cause of HCC in Sweden and to determine clinical characteristics associated with underlying MASLD. Using the Swedish quality registry for liver cancer (SweLiv), we identified all adults with a diagnosis of HCC in Sweden between 2012 and 2018. Baseline data were retrieved from SweLiv and other nationwide registers. Totally, 3494 patients with HCC were identified. Of them, 757 patients (22%) had MASLD-HCC. The proportion with MASLD-HCC increased from 19% in 2012 to 25% in 2018 (ptrend = 0.012), and MASLD was since 2017 the leading cause of HCC, surpassing hepatitis C. MASLD was the fastest growing cause of HCC with a 33% increment during the study period. Compared to other patients with HCC, those with MASLD-HCC were older (75 vs. 67 years, p < .001), less commonly had cirrhosis (61% vs. 82%, p < .001), had larger tumours (median 5.5 vs. 4.3 cm, p < .001), and more often extrahepatic metastasis (22% vs. 16%, p < .001). Patients with HCC caused by MASLD or by other causes were equally likely to be diagnosed in an early stage (Barcelona Clinic Liver Cancer 0-A, 27% vs. 30%, p = .129). MASLD is now the leading cause of HCC in Sweden.

Socioeconomic inequality in prostate cancer diagnostics, primary treatment, rehabilitation, and mortality in Sweden.

We designed a nationwide study to investigate the association between socioeconomic factors (household income and education) and different aspects of prostate cancer care, considering both individual- and neighbourhood-level variables. Data were obtained from Prostate Cancer data Base Sweden (PCBaSe), a research database with data from several national health care registers including clinical characteristics and treatments for nearly all men diagnosed with prostate cancer in Sweden. Four outcomes were analysed: use of pre-biopsy magnetic resonance imaging (MRI) in 2018-2020 (n = 11,843), primary treatment of high-risk non-metastatic disease in 2016-2020 (n = 6633), rehabilitation (≥2 dispensed prescriptions for erectile dysfunction within 1 year from surgery in 2016-2020, n = 6505), and prostate cancer death in 7770 men with high-risk non-metastatic disease diagnosed in 2010-2016. Unadjusted and adjusted odds and hazard ratios (OR/HRs) with 95% confidence intervals (CIs) were calculated. Adjusted odds ratio (ORs) comparing low versus high individual education were 0.74 (95% CI 0.66-0.83) for pre-biopsy MRI, 0.66 (0.54-0.81) for primary treatment, and 0.82 (0.69-0.97) for rehabilitation. HR gradients for prostate cancer death were significant on unadjusted analysis only (low vs. high individual education HR 1.41, 95% CI 1.17-1.70); co-variate adjustments markedly attenuated the gradients (low vs. high individual education HR 1.10, 95% CI 0.90-1.35). Generally, neighbourhood-level analyses showed weaker gradients over the socioeconomic strata, except for pre-biopsy MRI. Socioeconomic factors influenced how men were diagnosed with prostate cancer in Sweden but had less influence on subsequent specialist care. Neighbourhood-level socioeconomic data are more useful for evaluating inequality in diagnostics than in later specialist care.

Impact of organised colorectal cancer screening on age-specific population incidences: evidence from a quasi-experimental study in Sweden.

Colorectal cancer (CRC) incurs a significant disease burden globally. Organised CRC screening programmes have been widely implemented for early detection and prevention. To understand the public health impact of these programmes, quantitative evidence of changes in overall and age-specific population incidences is fundamental. We aimed to provide such evidence by exploiting a time lag in the implementation of organised screening in Sweden: two out of 21 regions (these two regions comprise nearly 20% of the total Swedish population) have offered organised screening since 2008; the other regions have offered CRC screening since 2021. Using registry data on diagnosed CRC cases and socio-demographics for all regions in Sweden over the period 1970-2019, Bayesian structural time series modelling and difference-in-differences were applied to analyse the impact of screening on age-specific population incidences over time (CRC cases per 100.000 persons/year). After inviting birth-year cohorts aged 60-69 years for stool-based testing, the incidence rate in the 70-74-year age group decreased significantly over time, with an average reduction of - 44·40 (95% CI - 58·15 to - 31·31) from 2011 to 2019 in the intervention regions. In the overall population aged 60-74 years, there was a net incidence decrease of - 7·99 (95% CI - 13·85 to - 2·39) since the initiation of organised screening in the intervention regions (2008-2019). Organised CRC screening for 60-69-year-olds generated a change in age-specific incidence patterns with a long-lasting incidence decrease in the 70-74-year-old population, implying reductions in the excess mortality and burden of the disease.

Unrecognized liver cirrhosis is common and associated with worse survival in hepatocellular carcinoma: A nationwide cohort study of 3473 patients.

BACKGROUND: Data on unrecognized liver cirrhosis in patients with hepatocellular carcinoma (HCC) are derived mainly from cohorts with a risk of selection bias. OBJECTIVES: In a population-based cohort study we aimed to determine the proportion, characteristics, and prognosis of HCC in patients with unrecognized cirrhosis. METHODS: Using the Swedish quality register for liver cancer and other nationwide registers, we identified all adults with HCC in Sweden between 2012 and 2018 (n = 3,473). RESULTS: The final study cohort comprised 2670 patients with established cirrhosis, of which 1033 (39%) had unrecognized cirrhosis at HCC diagnosis. These patients were more often male, older, and had larger tumors, multinodular cancer, portal vein thrombosis, and extrahepatic metastasis compared to patients with known cirrhosis with HCC and under surveillance (34%). Compared to surveilled patients, those with unrecognized cirrhosis had worse median survival (0.89 years, 95% confidence interval [CI] = 0.78-1.01 vs. 3.79 years, 95%CI = 3.19-4.39), and an adjusted hazard ratio of 2.36 (95%CI = 2.09-2.66). Patients with cirrhosis but not under surveillance (27%) and patients with unrecognized cirrhosis had similar characteristics, such as equal proportions diagnosed at late stage (79%). CONCLUSIONS: Cirrhosis is often not recognized in patients with HCC. Unrecognized cirrhosis is associated with more advanced HCC at diagnosis and a worse prognosis. More efforts are needed to diagnose cirrhosis at an earlier stage.

Can non-participants in a follow-up be used to draw conclusions about incidences and prevalences in the full population invited at baseline? An investigation based on the Swedish MDC cohort.

BACKGROUND: Participants in epidemiological cohorts may not be representative of the full invited population, limiting the generalizability of prevalence and incidence estimates. We propose that this problem can be remedied by exploiting data on baseline participants who refused to participate in a re-examination, as such participants may be more similar to baseline non-participants than what baseline participants who agree to participate in the re-examination are. METHODS: We compared background characteristics, mortality, and disease incidences across the full population invited to the Malmö Diet and Cancer (MDC) study, the baseline participants, the baseline non-participants, the baseline participants who participated in a re-examination, and the baseline participants who did not participate in the re-examination. We then considered two models for estimating characteristics and outcomes in the full population: one ("the substitution model") assuming that the baseline non-participants were similar to the baseline participants who refused to participate in the re-examination, and one ("the extrapolation model") assuming that differences between the full group of baseline participants and the baseline participants who participated in the re-examination could be extended to infer results in the full population. Finally, we compared prevalences of baseline risk factors including smoking, risky drinking, overweight, and obesity across baseline participants, baseline participants who participated in the re-examination, and baseline participants who did not participate in the re-examination, and used the above models to estimate the prevalences of these factors in the full invited population. RESULTS: Compared to baseline non-participants, baseline participants were less likely to be immigrants, had higher socioeconomic status, and lower mortality and disease incidences. Baseline participants not participating in the re-examination generally resembled the full population. The extrapolation model often generated characteristics and incidences even more similar to the full population. The prevalences of risk factors, particularly smoking, were estimated to be substantially higher in the full population than among the baseline participants. CONCLUSIONS: Participants in epidemiological cohorts such as the MDC study are unlikely to be representative of the full invited population. Exploiting data on baseline participants who did not participate in a re-examination can be a simple and useful way to improve the generalizability of prevalence and incidence estimates.

A comparison of small-area deprivation indicators for public-health surveillance in Sweden.

AIMS: The aims of this study were to construct a small-area index of multiple deprivation (IMD) from single deprivation indicators (SDIs) and to compare the explanatory power of the IMD and SDIs with regard to mortality. We considered a small-area division of Sweden consisting of 5985 DeSO (Demografiska statistikområden), each with a population size between 653 and 4243 at the end of 2018. METHODS: Four SDIs were provided by open-source data: (a) the proportion of inhabitants with a low economic standard; (b) the proportion of inhabitants aged 25-64 years with ⩽12 years of schooling; (c) the proportion of inhabitants aged 16-64 years who were not in paid employment; and (d) the proportion of inhabitants who lived in a rented apartment/house. A four-indicator IMD was constructed using factor analysis. As a validation, the IMD and SDIs were compared by exploring their DeSO-level associations with spatially smoothed death rates, with robustness checks of associations across different small-area contexts defined by degree of urbanisation and distribution of immigrants from non-Western countries. RESULTS: The constructed IMD and SDI1 performed essentially equally and outperformed SDI2, SDI3 and SDI4. Associations between IMD/SDI1 and the spatially smoothed death rates were most pronounced within the age range 60-79 years, showing 5-8% lowered rates among those categorised in the least deprived quintiles of IMD and SDI1, respectively, and 7-9% elevated rates among those categorised in the most deprived quintiles. These associations were consistent within each small-area context. CONCLUSIONS: We suggest prioritisation of SDI1, that is, a DeSO-level deprivation indicator based on open-access data on economic standard, for public-health surveillance in Sweden.

Community factors and excess mortality in the COVID-19 pandemic in England, Italy and Sweden.

BACKGROUND: Analyses of coronavirus disease 19 suggest specific risk factors make communities more or less vulnerable to pandemic-related deaths within countries. What is unclear is whether the characteristics affecting vulnerability of small communities within countries produce similar patterns of excess mortality across countries with different demographics and public health responses to the pandemic. Our aim is to quantify community-level variations in excess mortality within England, Italy and Sweden and identify how such spatial variability was driven by community-level characteristics. METHODS: We applied a two-stage Bayesian model to quantify inequalities in excess mortality in people aged 40 years and older at the community level in England, Italy and Sweden during the first year of the pandemic (March 2020-February 2021). We used community characteristics measuring deprivation, air pollution, living conditions, population density and movement of people as covariates to quantify their associations with excess mortality. RESULTS: We found just under half of communities in England (48.1%) and Italy (45.8%) had an excess mortality of over 300 per 100 000 males over the age of 40, while for Sweden that covered 23.1% of communities. We showed that deprivation is a strong predictor of excess mortality across the three countries, and communities with high levels of overcrowding were associated with higher excess mortality in England and Sweden. CONCLUSION: These results highlight some international similarities in factors affecting mortality that will help policy makers target public health measures to increase resilience to the mortality impacts of this and future pandemics.

Targeting population groups with heavier burden of hepatocellular carcinoma incidence: A nationwide descriptive epidemiological study in Sweden.

Contemporary European studies examining associations between socioeconomic status and hepatocellular carcinoma (HCC) incidence are scarce. We aimed to target population groups with a heavier burden of HCC by assessing associations of individual-level sociodemographic variables and neighbourhood deprivation with all-stage and stage-specific HCC incidence rates (IR). Patient and population data stratified by calendar year (2012-2018), sex, age (5-year groups), household income (low, medium and high), country of birth (Nordic, non-Nordic) and neighbourhood deprivation (national quintiles Q1-Q5) were retrieved from Swedish registers. HCC stages were defined by Barcelona Clinic Liver Cancer stages 0 to A (early-stage) and B to D (late-stage). IR (per 100 000 person-years) were estimated by Poisson regression models. Men had four times higher IR than women. IRs increased markedly with lower household income as well as with neighbourhood deprivation. Seven times higher IR was observed among people with a low household income living in the most deprived neighbourhoods (IR 3.90, 95% confidence interval [CI] 3.28-4.64) compared to people with a high household income living in the least deprived neighbourhoods (IR 0.58, 95% CI 0.46-0.74). The gradient across income categories was more pronounced for late-stage than early-stage HCC. IR reached 30 (per 100 000 person-years) for people in the age span 60 to 79 years with low income and 20 for 60 to 79 year old people living in the most deprived neighbourhoods (regardless of income). Men with low household income and/or living in the most deprived neighbourhoods might be considered as primary targets in studies evaluating the cost-effectiveness of screening for early-stage HCC detection.

Factors predicting participation and potential yield of screening-detected disease among non-participants in a Swedish population-based atrial fibrillation screening study.

BACKGROUND: The success of any screening program is dependent on participation. The characteristics of participants vs. non-participants have been studied and non-participants usually have a higher risk of disease. The potential yield of screening-detected disease in non-participants could be of interest to several screening programs. AIMS: This is a sub-study to STROKESTOP II, a Swedish atrial fibrillation screening study. The aim was to study factors predicting participation and to estimate the potential yield of screening-detected disease in non-participants. METHODS: Individual, anonymized data for participants and non-participants with respect to socioeconomic factors, medical history and drugs dispensed were obtained from Swedish registries. A random forest model was trained to predict propensity scores for participation. The propensity scores were used to estimate potential screening-detected disease among non-participants. RESULTS: Non-participants (n = 7086) had lower income, were more likely to have been hospitalized and had higher CHA2DS2-VASc scores compared to participants (n = 6868). The strongest factor predicting non-attendance was low income. The weighted estimates suggested that the yield of new atrial fibrillation was 2.4% in non-participants compared to 2.3% in the participants, which was not significant. CONCLUSIONS: Non-participants had higher CHA2DS2-VASc scores, indicating a higher stroke-risk and presumable benefit from attending screening, although estimated new atrial fibrillation detected was not significantly more common when compared to participants. Low income was the strongest factor for predicting non-attendance and should be a focus area when planning future screening scenarios.

Correcting for selective participation in cohort studies using auxiliary register data without identification of non-participants.

Aims: Selective participation may hamper the validity of population-based cohort studies. The resulting bias can be alleviated by linking auxiliary register data to both the participants and the non-participants of the study, estimating propensity scores for participation and correcting for participation based on these. However, registry holders may not be allowed to disclose sensitive data on (invited) non-participants. Our aim is to provide guidance on how adequate bias correction can be achieved by using auxiliary register data but without disclosing information that could be linked to the subset of non-participants. Methods: We show how existing methods can be used to estimate generalisation weights under various data disclosure scenarios where invited non-participants are indistinguishable from uninvited ones. We also demonstrate how the methods can be implemented using Nordic register data. Results: Inverse-probability-of-sampling weights estimated within a random sample of the target population in which the non-respondents are disclosed are equivalent in expectation to analogous weights in a scenario where the non-participants and uninvited individuals from the population are indistinguishable. To minimise the risk of disclosure when the entire population is invited to participate, investigators should instead consider inverse-odds-of-sampling weights, a method that has previously been suggested for transporting study results to external populations. Conclusions: Generalisation weights can be estimated from auxiliary register data without disclosing information on invited non-participants.

A novel framework for classification of selection processes in epidemiological research.

BACKGROUND: Selection and selection bias are terms that lack consistent definitions and have varying meaning and usage across disciplines. There is also confusion in current definitions between underlying mechanisms that lead to selection and their consequences. Consequences of selection on study validity must be judged on a case-by-case basis depending on research question, study design and analytical decisions. The overall aim of the study was to develop a simple but general framework for classifying various types of selection processes of relevance for epidemiological research. METHODS: Several original articles from the epidemiological literature and from related areas of observational research were reviewed in search of examples of selection processes, used terminology and description of the underlying mechanisms. RESULTS: We classified the identified selection processes in three dimensions: i) selection level (selection at the population level vs. study-specific selection), ii) type of mechanism (selection in exposure vs. selection in population composition), iii) timing of the selection (at exposure entry, during exposure/follow-up or post-outcome). CONCLUSIONS: Increased understanding of when, how, and why selection occur is an important step towards improved validity of epidemiological research.

Incidence, aetiology and related comorbidities of cirrhosis: a Swedish population-based cohort study.

BACKGROUND: The incidence of cirrhosis for individuals in Sweden has previously been reported as stable/low among European countries. However, Swedish population-based studies are scarce and none of them included data from the most recent decade (2010-2019). We aimed to describe the incidence and aetiology of cirrhosis in the Halland region from 2011 to 2018, and to describe the severity and prevalence of liver-related complications and other primary comorbidities at the time of cirrhosis diagnosis. METHODS: We conducted a retrospective cohort study of all patients with cirrhosis in Halland, which has a population of 310,000 inhabitants. Medical records and histopathology registries were reviewed. RESULTS: A total of 598 patients with cirrhosis were identified. The age-standardised incidence was estimated at 23.2 per 100,000 person-years (95% CI 21.3-25.1), 30.5 (95% CI 27.5-33.8) for men and 16.4 (95% CI 14.3-18.7) for women. When stratified by age, the highest incidence rates were registered at age 60-69 years. Men had a higher incidence rate for most age groups when compared to women. The most common aetiology was alcohol (50.5%), followed by cryptogenic cirrhosis (14.5%), hepatitis C (13.4%), and non-alcoholic fatty liver disease (5.7%). Most patients had at least one liver-related complication at diagnosis (68%). The most common comorbidities at diagnosis were arterial hypertension (33%), type 2 diabetes (29%) and obesity (24%). CONCLUSIONS: Based on previous Swedish studies, our results indicate that the incidence of cirrhosis in Sweden might be considerably higher than previously reported. It is uncertain if the incidence of cirrhosis has previously been underestimated or if an actual increment has occurred during the course of the most recent decade. The increased incidence rates of cirrhosis reported in Halland are multifactorial and most likely related to higher incidence rates among the elderly. Pre-obesity and obesity are common in cirrhosis and non-alcoholic fatty liver disease has become an important cause of cirrhosis in Halland.

Disease mapping of early- and late-stage cancer to monitor inequalities in early detection: a study of cutaneous malignant melanoma.

We consider disease mapping of early- and late-stage cancer, in order to identify and monitor inequalities in early detection. Our method is demonstrated by mapping cancer incidence at high geographical resolution using data on 10,302 cutaneous malignant melanoma (CMM) cases within the 3.7 million population of South-West Sweden. The cases were geocoded into small-areas, each with a population size between 600 and 2600 and accessible socio-demographic data. Using the disease mapping application Rapid Inquiry Facility (RIF) 4.0, we produced regional maps to visualise spatial variations in stage I, II and III-IV CMM incidences, complemented by local maps to explore the variations within two urban areas. Pronounced spatial disparities in stage I CMM incidence were revealed by the regional and local maps. Stage I CMM incidence was markedly higher in wealthier small-areas, in particular within each urban area. A twofold higher stage I incidence was observed, on average, in the wealthiest small-areas (upper quintile) than in the poorest small-areas (lower quintile). We identified in the regional map of stage III-IV CMM two clusters of higher or lower than expected late-stage incidences which were quite distinct from those identified for stage I. In conclusion, our analysis of CMM incidences supported the use of this method of cancer stage incidence mapping for revealing geographical and socio-demographic disparities in cancer detection.

Can the validity of a cohort be improved by reweighting based on register data? Evidence from the Swedish MDC study.

BACKGROUND: In any study with voluntary participation, self-selection risks leading to invalid conclusions. If the determinants of selection are observed, it is however possible to restore the parameters of interest by reweighting the sample to match the population, but this approach has seldom been applied in epidemiological research. METHODS: We reweighted the Malmö Diet and Cancer (MDC) study based on population register data on background variables, including socio-demographics and hospital admissions for both participants and the background population. Following individuals from baseline in 1991-1996 and at most until 2016, we studied mortality (all-cause, cancer, and CVD), incidences (cancer and CVD), and associations between these outcomes and background variables. Results from the unweighted and reweighted participant sample were compared with those from the background population. RESULTS: Mortality was substantially lower in participants than in the background population, but reweighting the sample helped only little to make the numbers similar to those in the background population. For incidences and associations, numbers were generally similar between participants and the background population already without reweighting, rendering reweighting unnecessary. CONCLUSION: Reweighting samples based on an extensive range of sociodemographic characteristics and previous hospitalizations does not necessarily yield results that are valid for the population as a whole. In the case of MDC, there appear to be important factors related to both mortality and selection into the study that are not observable in registry data, making it difficult to obtain accurate numbers on population mortality based on cohort participants. These issues seem less relevant for incidences and associations, however. Overall, our results suggest that representativeness must be judged on a case-by-case basis.

Socioeconomic and marital status among liver cirrhosis patients and associations with mortality: a population-based cohort study in Sweden.

BACKGROUND: The importance of socioeconomic status for survival in cirrhosis patients is more or less pronounced within different populations, most likely due to cultural and regional differences combined with dissimilarities in healthcare system organisation and accessibility. Our aim was to study the survival of patients with cirrhosis in a population-based Swedish cohort, using available data on marital status, employment status, and occupational skill level. METHODS: We conducted a retrospective cohort study of 582 patients diagnosed with cirrhosis in the Region of Halland (total population 310,000) between 2011 and 2018. Medical and histopathologic data, obtained from registries, were reviewed. Cox regression models were used to estimate associations between survival and marital status (married, never married, previously married), employment status (employed, pensioner, disability retired, unemployed), and occupational skill level (low-skilled: level I; medium-skilled: level II; medium-high skilled: level III; professionals: level IV); adjusting for sex, age, aetiology, Model for End-stage Liver Disease (MELD) score, Child-Pugh class, and comorbidities. RESULTS: Alcohol was the most common aetiology (51%). Most patients were male (63%) and the median age was 66 years. Occupational skill level was associated with the severity of cirrhosis at diagnosis and the prevalence of Child-Pugh C gradually increased from professionals through low-skilled. The mean survival for professionals (6.39 years, 95% CI 5.54-7.23) was higher than for low-skilled (3.00 years, 95% CI 2.33-3.67) and medium-skilled (4.04 years, 95% CI 3.64-4.45). The calculated hazard ratios in the multivariate analysis were higher for low-skilled (3.43, 95% CI 1.89-6.23) and medium-skilled (2.48, 95% CI 1.48-4.12), compared to professionals. When aggregated, low- and medium-skilled groups also had poorer mean survival (3.79 years, 95% CI 3.44-4.14; vs 5.64 years, 95% CI 5.00-6.28) and higher hazard ratios (1.85, 95% CI 1.32-2.61) compared to the aggregated medium-high skilled and professional groups. Marital and employment status were not statistically significant predictors of mortality in the multivariate analysis. CONCLUSIONS: Occupational skill level was strongly associated with mean survival and mortality risk. Poorer prognosis among patients with low and medium occupational skill level could not be explained by differences in sex, age, marital status, employment status, MELD score, Child-Pugh class, or comorbidity.

Sociodemographic disparities in stage-specific incidences of endometrial cancer: a registry-based study in West Sweden, 1995-2016.

Background: For a few types of cancer, lower socioeconomic status (SES) is associated with higher incidence, and for even more cancer types it is associated with having a less favorable tumor stage at diagnosis. For endometrial cancer (EC), however, there is no clear evidence of such associations with SES. There is a need for analysis of sociodemographic disparities in EC incidences according to stage at diagnosis, which may provide support for trying to improve early detection of EC. Material and methods: Stage-specific incidences of endometrioid and non-endometrioid endometrial carcinomas [EECs (∼90% of all EC cases) and NECs (∼10%)] were analyzed for the population of the Western Swedish Healthcare Region, taking into account year (1995-2016), age, educational level (low, intermediate and high), and immigrant status (Swedish-born, foreign-born). All EC cases were identified and data were obtained from population-based registries. Results: Stage distribution of diagnosed EECs differed significantly according to the educational level of patients who were aged between 50 and 74 years at diagnosis, but not in the case of younger or older patients. An analysis based on 3113 EEC cases aged 50-74 years at diagnosis revealed marked disparities in the stage-II to stage-IV EEC incidences but not in the stage-I EEC incidence. Compared to women with a high level of education, the incidence rate ratios of stage-I, stage-II and stage-III and -IV EEC in women with a low level of education were 1.00 (95% CI: 0.90-1.12), 1.65 (1.13-2.42), and 1.82 (1.33-2.49), respectively. For NEC, we found no such association. Conclusions: Elevated incidences of stage-II to stage-IV EEC in 50- to 74-year-old women with a low level of education suggest that there should be targeted health service trials aimed at improving awareness of EC. Well-targeted EC awareness programs might lead to considerable health benefits.

Assessing heterogeneous effects and their determinants via estimation of potential outcomes.

When analyzing effect heterogeneity, the researcher commonly opts for stratification or a regression model with interactions. While these methods provide valuable insights, their usefulness can be somewhat limited, since they typically fail to take into account heterogeneity with respect to many dimensions simultaneously, or give rise to models with complex appearances. Based on the potential outcomes framework and through imputation of missing potential outcomes, our study proposes a method for analyzing heterogeneous effects by focusing on treatment effects rather than outcomes. The procedure is easy to implement and generates estimates that take into account heterogeneity with respect to all relevant dimensions at the same time. Results are easily interpreted and can additionally be represented by graphs, showing the overall magnitude and pattern of heterogeneity as well as how this relates to different factors. We illustrate the method both with simulations and by examining heterogeneous effects of obesity on HDL cholesterol in the Malmö Diet and Cancer cardiovascular cohort. Obesity was associated with reduced HDL in almost all individuals, but effects varied with smoking, risky alcohol consumption, higher education, and energy intake, with some indications of non-linear effects. Our approach can be applied by any epidemiologist who wants to assess the role and strength of heterogeneity with respect to a multitude of factors.

DNA ploidy status, S-phase fraction, and p53 are not independent prognostic factors for survival in endometrioid endometrial carcinoma FIGO stage I-III.

OBJECTIVES: To assess the effects on relative survival of established and new prognostic factors in stage I-III grade 1-3 endometrioid endometrial carcinoma and in the subgroup of stage I grade 1-2. METHODS: This was a population-based, retrospective study including all women (n=1113) in the western Swedish healthcare region diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage I-III grade 1-3 endometrioid endometrial carcinoma in 2006-2011. Histology, grade, stage, and age were prospectively reported to the regional clinical and national cancer registers. DNA ploidy and S-phase fraction were analyzed by flow cytometer. S-phase fraction cut-off was set at ≥8%. Tumor biopsies were classified as diploid if there was one G0/G1 peak or the DNA index was 1.0±0.04. Overexpression of p53 as determined by immunohistochemistry was positive if strong nuclear staining was found in >30% of the neoplastic cells. RESULTS: Based on univariable statistical analyses we found that 5-year relative survival was significantly associated with S-phase fraction, DNA ploidy, p53, stage, grade, and age. Excess mortality for S-phase fraction ≥8%, aneuploidy, and p53 overexpression was 8, 14, and 8 and times higher, respectively. However, in a multivariable regression model, adjusted for stage, grade, and age, S-phase fraction, DNA ploidy, and p53 were not statistically independent prognostic factors (p=0.413, p=0.107, p=0.208, respectively) for 5-year relative survival in stage I-III grade 1-3 endometrioid endometrial carcinoma. In a subgroup analysis of stage I grade 1-2, aneuploidy identified a subgroup with impaired 5-year relative survival. CONCLUSION: We can conclude that S-phase fraction, DNA ploidy, and p53 overexpression did not improve identification of high-risk patients by stage, grade, and age in stage I-III endometrioid endometrial carcinoma. In stage I, aneuploidy and grade 2 predicted lower relative survival rates than other variables.

A prospective 5-year follow-up after population-based systematic screening for atrial fibrillation.

Aims: Thrombo-embolic stroke risk in atrial fibrillation (AF) is significantly reduced with oral anticoagulant (OAC) treatment. Atrial fibrillation is often asymptomatic (silent) and therefore undiagnosed. The long-term course of silent AF as well as OAC treatment adherence after AF screening is not known. We aim at studying long-term adherence to OAC treatment, AF symptoms, and stroke incidence on population level after systematic AF screening. Methods and results: All inhabitants in a Swedish municipality who were born in 1934 and 1935 (n = 1335) were invited to participate in an AF screening trial between 2010 and 2012. Participants with a previously known or screening-detected AF were invited to a 5-year follow-up. Time trends of ischaemic stroke incidence were compared for population groups residing in the intervention municipality and in a surrounding control area where no AF screening trial was carried out. After the screening procedure, 103 of 121 participants (85%) with AF were treated with OAC. At the follow-up examination, 94 of 106 living patients (88%) were still on OAC treatment. Among the 23 long-term surviving patients who were diagnosed with paroxysmal AF during screening, 6 had developed permanent silent AF. The incidence of ischaemic stroke between ages 76-80 years declined significantly after the AF screening trial in the intervention area (P = 0.003) but not in the control area. Conclusion: Adherence to OAC treatment 5 years after AF screening was high. Silent AF has a natural course similar to symptomatic AF. The observed incidences of ischaemic stroke suggest a beneficial population-level effect of systematic AF screening.