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Background: Irregular legal status is a recognized health risk factor in the context of migration. However, undocumented migrants are rarely included in health surveys and register studies. Adverse perinatal outcomes are especially important because they have long-term consequences and societal risk factors are modifiable. In this study, we compare perinatal outcomes in undocumented migrants to foreign-born and Norwegian-born residents, using a population-based register., Methods: We included women 18-49 years old giving birth to singletons as registered in the Medical Birth Registry of Norway from 1999 to 2020. Women were categorized as 'undocumented migrants' (without an identity number), 'documented migrants' (with an identity number and born abroad), and 'non-migrants' (with an identity number and born in Norway). The main outcome was perinatal mortality, i.e., death of a foetus ≥ gestational week 22, or neonate up to seven days after birth. We used log-binominal regression to estimate the association between legal status and perinatal mortality, adjusting for several maternal pre-gestational and gestational factors. Direct standardization was used to adjust for maternal region of origin., Ethical Approval: Regional Ethical Committee (REK South East, case number 68329)., Results: We retrieved information on 5856 undocumented migrant women who gave birth during the study period representing 0.5% of the 1 247 537 births in Norway. Undocumented migrants had a relative risk of 6.17 (95% confidence interval 5.29 ̶7.20) of perinatal mortality compared to non-migrants and a relative risk of 4.17 (95% confidence interval 3.51 ̶4.93) compared to documented migrants. Adjusting for maternal region of origin attenuated the results slightly., Conclusion: Being undocumented is strongly associated with perinatal mortality in the offspring. Disparities were not explained by maternal origin or maternal health factors, indicating that social determinants of health through delays in receiving adequate care and factors negatively influencing gestational length may be of importance., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Additive frailty models are used to model correlated survival data. However, the complexity of the models increases with cluster size to the extent that practical usage becomes increasingly challenging. We present a modification of the additive genetic gamma frailty (AGGF) model, the lean AGGF (L-AGGF) model, which alleviates some of these challenges by using a leaner additive decomposition of the frailty. The performances of the models were compared and evaluated in a simulation study. The L-AGGF model was used to analyze population-wide data on clustering of melanoma in 2 391 125 two-generational Norwegian families, 1960-2015. Using this model, we could analyze the complete data set, while the original model limited the analysis to a restricted data set (with cluster sizes ≤ 7 $$ \le 7 $$ ). We found a substantial clustering of melanoma in Norwegian families and large heterogeneity in melanoma risk across the population, where 52% of the frailty was attributed to the 10% of the population at highest unobserved risk. Due to the improved scalability, the L-AGGF model enables a wider range of analyses of population-wide data compared to the AGGF model. Moreover, the methods outlined here make it possible to perform these analyses in a computationally efficient manner., (© 2023 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.)

Despite substantial geographical variation in cardiovascular (CVD) mortality within countries, little is known about whether this variation can be explained by individuals' life course socioeconomic position (SEP) or differences in family history of premature CVD deaths. Cox proportional hazards models were used to investigate the association between the county of residence at ages 50-59 and CVD death in Norwegians born between 1940 and 1959 and survived to at least age 60, using national data. Individual life course SEP and family history of premature CVD death reduced the geographical variation in CVD mortality across Norwegian counties, but some significant differences remained. Furthermore, CVD risk varied by residents' migration histories between two counties with distinct CVD and socioeconomic profiles., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: M. LeBlanc has served as speaker for MSD outside the submitted work., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: SARS-CoV-2 mRNA vaccination has been associated with both side effects and a reduction in COVID-related complaints due to the decrease in COVID-19 incidence. We aimed to investigate if individuals who received three doses of SARS-CoV-2 mRNA vaccines had a lower incidence of (a) medical complaints and (b) COVID-19-related medical complaints, both as seen in primary care, when compared to individuals who received two doses., Methods: We conducted a daily longitudinal exact one-to-one matching study based on a set of covariates. We obtained a matched sample of 315,650 individuals aged 18-70 years who received the 3rd dose at 20-30 weeks after the 2nd dose and an equally large control group who did not. Outcome variables were diagnostic codes as reported by general practitioners or emergency wards, both alone and in combination with diagnostic codes of confirmed COVID-19. For each outcome, we estimated cumulative incidence functions with hospitalization and death as competing events., Results: We found that the number of medical complaints was lower in individuals aged 18-44 years who received three doses compared to those who received two doses. The differences in estimates per 100,000 vaccinated were as follows: fatigue 458 less (95% confidence interval: 355-539), musculoskeletal pain 171 less (48-292), cough 118 less (65-173), heart palpitations 57 less (22-98), shortness of breath 118 less (81-149), and brain fog 31 less (8-55). We also found a lower number of COVID-19-related medical complaints: per 100,000 individuals aged 18-44 years vaccinated with three doses, there were 102 (76-125) fewer individuals with fatigue, 32 (18-45) fewer with musculoskeletal pain, 30 (14-45) fewer with cough, and 36 (22-48) fewer with shortness of breath. There were no or fewer differences in heart palpitations (8 (1-16)) or brain fog (0 (- 1-8)). We observed similar results, though more uncertain, for individuals aged 45-70 years, both for medical complaints and for medical complaints that were COVID-19 related., Conclusions: Our findings suggest that a 3rd dose of SARS-CoV-2 mRNA vaccine administered 20-30 weeks after the 2nd dose may reduce the incidence of medical complaints. It may also reduce the COVID-19-related burden on primary healthcare services., (© 2023. The Author(s).)

Little is known about if and how nevi and pigmentation are associated with melanoma-specific mortality. However, increased melanoma awareness in people with lighter pigmentation and many nevi may result in earlier diagnosis of thinner less-lethal tumors. The aim of this study was to investigate associations between nevus count (asymmetrical > 5 mm and small symmetrical), pigmentary characteristics (hair colour, eye colour, skin colour, freckling, pigmentary score), and melanoma-specific mortality in subjects with melanomas > 1 mm. Data from the Norwegian Women and Cancer cohort, established in 1991, with complete follow-up of melanoma patients until 2018 through the Cancer Registry of Norway, were used to estimate hazard ratios with 95% confidence intervals for the associations between nevus count, pigmentary characteristics, and melanoma-specific mortality, stratified by tumor thickness using Cox regression. Estimated hazard ratios consistently indicated a higher risk of melanoma death for those with darker vs lighter pigmentary characteristics in patients with tumors > 1.0-2.0 mm and > 2.0 mm thick (e.g. pigmentary score hazard ratio 1.25, 95% confidence interval (0.74-2.13)). Among women with melanomas > 1.0 mm thick, lighter pigmentation and asymmetrical nevi may be associated with lower melanoma-specific mortality, suggesting that factors that increase the risk of melanoma may also be associated with decreased risk of death from melanoma.

In a recently published paper in BMC Public Health we read about a randomized trial on Covid-19 transmission performed in five fitness centers in Oslo, Norway, during the spring of 2020. In our opinion, this study has major shortcomings in design and methodology, which have not been addressed by the authors., (© 2022. The Author(s).)

Introduction: Familial support may be important for post-stroke survival., Objective: To determine if geographical proximity between stroke survivors and their family members, i.e having a spouse/partner or distance to a nearest first-degree relative (parents, siblings, and offspring), as a proxy for familial support, is related to survivor mortality., Methods: This study included all stroke survivors (n=128,227) hospitalised in Norway from 1994 to 2009, who were 30 years or older at the time of the stroke (born before 1965). National registries and censuses were used to calculate the distance to the nearest first-degree relative in the hospitalisation year. Cox proportional hazards models estimated hazard ratios (HRs) of all-cause mortality from 1994 to 2014 (mean 6.4 years follow-up), adjusting for sociodemographic and clinical covariates., Results: Living up to 30 km from the nearest first-degree relative was associated with a higher mortality (HR 1.04, 95% CI: 1.03 to 1.06) than those living in the same household or neighbourhood as their nearest first-degree relatives. The association was more pronounced (1.13, 1.08 to 1.19 for ≤30 km; 1.25, 1.16 to 1.35 for >30 km) in survivors hospitalised at age ≤65 years, compared to older survivors. Among familial care predictors, having a spouse/partner was the most prominent predictor of reduced mortality (0.80, 0.78 to 0.82) in stroke survivors., Conclusion: Living close to first-degree relatives was weakly associated with better survival in stroke patients while having a spouse/partner exhibited a stronger association. Both associations were larger for survivors hospitalised at age ≤65 years. Our findings thus suggest that the impact of familial support on survival after stroke may differ by familial support condition and patient's age at a stroke hospitalisation., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aims: To measure and evaluate clinical response to nasal naloxone in opioid overdoses in the pre-hospital environment., Design: Randomised, controlled, double-dummy, blinded, non-inferiority trial, and conducted at two centres., Setting: Participants were included by ambulance staff in Oslo and Trondheim, Norway, and treated at the place where the overdose occurred., Participants: Men and women age above 18 years with miosis, rate of respiration ≤8/min, and Glasgow Coma Score <12/15 were included. Informed consent was obtained through a deferred-consent procedure., Intervention and Comparator: A commercially available 1.4 mg/0.1 mL intranasal naloxone was compared with 0.8 mg/2 mL naloxone administered intramuscularly., Measurements: The primary end-point was restoration of spontaneous respiration of ≥10 breaths/min within 10 minutes. Secondary outcomes included time to restoration of spontaneous respiration, recurrence of overdose within 12 hours and adverse events., Findings: In total, 201 participants were analysed in the per-protocol population. Heroin was suspected in 196 cases. With 82% of the participants being men, 105 (97.2%) in the intramuscular group and 74 (79.6%) in the intranasal group returned to adequate spontaneous respiration within 10 minutes after one dose. The estimated risk difference was 17.5% (95% CI, 8.9%-26.1%) in favour of the intramuscular group. The risk of receiving additional naloxone was 19.4% (95% CI, 9.0%-29.7%) higher in the intranasal group. Adverse reactions were evenly distributed, except for drug withdrawal reactions, where the estimated risk difference was 6.8% (95% CI, 0.2%-13%) in favour of the intranasal group in a post hoc analysis., Conclusion: Intranasal naloxone (1.4 mg/0.1 mL) was less efficient than 0.8 mg intramuscular naloxone for return to spontaneous breathing within 10 minutes in overdose patients in the pre-hospital environment when compared head-to-head. Intranasal naloxone at 1.4 mg/0.1 mL restored breathing in 80% of participants after one dose and had few mild adverse reactions., (© 2022 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Background: In March 2020, WHO announced the COVID-19 a pandemic and a major global public health emergency. Mortality from COVID-19 is rapidly increasing globally, with acute respiratory failure as the predominant cause of death. Many patients experience severe hypoxia and life-threatening respiratory failure often requiring mechanical ventilation. To increase safety margins during emergency anaesthesia and rapid sequence intubation (RSI), patients are preoxygenated with a closed facemask with high-flow oxygen and positive end-expiratory pressure (PEEP). Due to the high shunt fraction of deoxygenated blood through the lungs frequently described in COVID-19 however, these measures may be insufficient to avoid harmful hypoxemia. Preoxygenation with inhaled nitric oxide (iNO) potentially reduces the shunt fraction and may thus allow for the necessary margins of safety during RSI., Methods and Design: The INOCOV protocol describes a phase II pharmacological trial of inhaled nitric oxide (iNO) as an adjunct to standard of care with medical oxygen in initial airway and ventilation management of patients with known or suspected COVID-19 in acute respiratory failure. The trial is parallel two-arm, randomized, controlled, blinded trial. The primary outcome measure is the change in oxygen saturation (SpO2), and the null hypothesis is that there is no difference in the change in SpO2 following initiation of iNO., Trial Registration: EudraCT number 2020-001656-18; WHO UTN: U1111-1250-1698. Protocol version: 2.0 (June 25th, 2021)., Competing Interests: The authors have declared that no competing interests exist.

Background: Whether surgical repair of an acute Achilles' tendon rupture by an open-repair or minimally invasive approach is associated with better outcomes than nonsurgical treatment is not clear., Methods: We performed a multicenter, randomized, controlled trial that compared nonoperative treatment, open repair, and minimally invasive surgery in adults with acute Achilles' tendon rupture who presented to four trial centers. The primary outcome was the change from baseline in the Achilles' tendon Total Rupture Score (scores range from 0 to 100, with higher scores indicating better health status) at 12 months. Secondary outcomes included the incidence of tendon rerupture., Results: A total of 554 patients underwent randomization, and 526 patients were included in the final analysis. The mean changes in the Achilles' tendon Total Rupture Score were -17.0 points in the nonoperative group, -16.0 points in the open-repair group, and -14.7 points in the minimally invasive surgery group (P = 0.57). Pairwise comparisons provided no evidence of differences between the groups. The changes from baseline in physical performance and patient-reported physical function were similar in the three groups. The number of tendon reruptures was higher in the nonoperative group (6.2%) than in the open-repair or minimally invasive surgery group (0.6% in each). There were 9 nerve injuries in the minimally invasive surgery group (in 5.2% of the patients) as compared with 5 in the open-repair group (in 2.8%) and 1 in the nonoperative group (in 0.6%)., Conclusions: In patients with Achilles' tendon rupture, surgery (open repair or minimally invasive surgery) was not associated with better outcomes than nonoperative treatment at 12 months. (Funded by the South-Eastern Norway Regional Health Authority and Akershus University Hospital; ClinicalTrials.gov number, NCT01785264.)., (Copyright © 2022 Massachusetts Medical Society.)

Introduction: Intranasal (IN) naloxone is widely used to treat opioid overdoses. The advantage of nasal administration compared with injection lies in its suitability for administration by lay people as it is needless. Approved formulations of nasal naloxone with bioavailability of approximately 50% have only undergone trials in healthy volunteers, while off-label nasal sprays with low bioavailability have been studied in patients. Randomised clinical trials are needed to investigate efficacy and safety of approved IN naloxone in patients suffering overdose. This study investigates whether the administration of 1.4 mg naloxone in 0.1 mL per dose is non-inferior to 0.8 mg intramuscular injection in patients treated for opioid overdose., Methods and Analysis: Sponsor is the Norwegian University of Science and Technology. The study has been developed in collaboration with user representatives. The primary endpoint is the restoration of spontaneous respiration≥10 breaths/min based on a sample of 200 opioid overdose cases. Double-dummy design ensures blinding, which will be maintained until the database is locked., Ethics and Dissemination: The study was approved by the Norwegian Medicines Agency and Regional Ethics Committees (REC: 2016/2000). It adheres to the Good Clinical Practice guidelines as set out by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use.Informed consent will be sought through a differentiated model. This allows for deferred consent after inclusion for patients who have regained the ability to consent. Patients who are unable to consent prior to discharge by emergency services are given written information and can withdraw at a later date in line with user recommendations. Metadata will be published in the Norwegian University of Science and Technology Open repository. Deidentified individual participant data will be made available to recipients conditional of data processor agreement being entered., Trial Registration Numbers: EudraCT Registry (2016-004072-22) and Clinicaltrials.gov Registry (NCT03518021)., Competing Interests: Competing interests: The contents and production of study kits are funded by dne pharma as, Oslo, Norway. Norwegian University of Science and Technology (NTNU) and its subsidiary Technical Transfer Office have signed cooperative and licensing contracts with dne pharma as to seek commercialisation of this nasal naloxone formulation. This regulates potential royalties for OD through NTNU. dne pharma as has compensated OD for business travel from Trondheim to Oslo and to Lisbon. AKS spoke at a seminar arranged by dne pharma as in Lisbon in October 2019 without an honorarium or other compensation. The other authors declare no conflicts of interest. The funding sources have no role in the study design, data collection, data analysis, data interpretation or writing of the clinical study report., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Low back pain is common and a significant number of patients experience chronic low back pain. Current treatment options offer small to moderate effects. Patients with vertebral bone marrow lesions visualized as Modic changes on magnetic resonance imaging may represent a subgroup within the low back pain population. There is evidence for inflammatory mediators being involved in development of Modic changes; hence, suppression of inflammation could be a treatment strategy for these patients. This study examines the effect of anti-inflammatory treatment with the TNF-α inhibitor infliximab in patients with chronic low back pain and Modic changes., Methods/design: The BackToBasic trial is a multicenter, double blind, randomized controlled trial conducted at six hospitals in Norway, comparing intravenous infusions with infliximab with placebo. One hundred twenty-six patients aged 18-65 with chronic low back pain and type 1 Modic changes will be recruited from secondary care outpatients' clinics. The primary outcome is back pain-specific disability at day 154 (5 months). The study is designed to detect a difference in change of 10 (SD 18) in the Oswestry Disability Index at day 154/ 5 months. The study also aims to refine MRI-assessment, investigate safety and cost-effectiveness and explore the underlying biological mechanisms of Modic changes., Discussion: Finding treatments that target underlying mechanisms could pose new treatment options for patients with low back pain. Suppression of inflammation could be a treatment strategy for patients with low back pain and Modic changes. This paper presents the design of the BackToBasic study, where we will assess the effect of an anti-inflammatory treatment versus placebo in patients with chronic low back pain and type 1 Modic changes. The study is registered at ClinicalTrials.gov under the identifier NCT03704363 . The EudraCT Number: 2017-004861-29.

Importance: With increasing prevalence of atopic dermatitis (AD) and its manifestation in most countries, together with the supporting evidence of the progression to other atopic phenotypes, AD has developed into a worldwide public health concern. The presence of the disease of has increased since the 1950s, but some recent studies suggest a stationary or decreasing trend., Objective: To analyze a nationwide health register based on prescription data to determine the incidence rate (IR) of AD in an entire pediatric population., Design, Setting, and Participants: All children resident in Norway younger than 6 years from January 1, 2009, through December 31, 2015, were included in this cohort study. Medical diagnoses and disease-specific medications were used as a proxy for identifying children with AD in this population-based prescription registry study. The prescription study was terminated in 2016. The total number of 295 286 disease-specific prescriptions was analyzed from August 2016 through December 2017. The hypothesis was formulated before, during, and after the data collection., Main Outcomes and Measures: All children with a medical diagnosis of AD or eczema based on at least 2 prescriptions of topical corticosteroids or at least 1 prescription of topical calcineurin inhibitors. Incidence rates per person-year (PY) and IR ratios were calculated., Results: A total of 295 286 disease-specific prescriptions were dispensed to 122 470 children, of whom 63 460 had AD and 56 009 (88.3%) had reimbursed prescriptions and associated AD diagnoses. The annual Norwegian study population (aged <6 years) increased from 357 451 children in 2009 to 373 954 in 2015. The overall IR increased from 0.028 per PY (95% CI, 0.028-0.029 per PY) in 2009 to 0.034 per PY (95% CI, 0.033-0.035 per PY) in 2014. For children younger than 1 year, the IR increased from 0.052 per PY (95% CI, 0.050-0.053 PY) in 2009 to 0.073 per PY (95% CI, 0.071-0.075 per PY) in 2014. In this age group, the IR was 53% higher in boys compared with girls (IR ratio, 1.53; 95% CI, 1.49-1.57; P < .001). The incidence proportion before the age of 6 years was 17.4% (95% CI, 17.2%-17.7%). The primary seasons for the onset of AD were winter and spring., Conclusions and Relevance: This nationwide study suggests an increase in the IR of pediatric AD, especially among children younger than 1 year. This study's findings suggest that increase occurred with a higher IR during winter and spring seasons. Atopic dermatitis had an earlier onset in boys than in girls. During the study period, more than 1 in 6 children younger than 6 years had, at some point, been affected by AD.

Background: A wide range of diseases show some degree of clustering in families; family history is therefore an important aspect for clinicians when making risk predictions. Familial aggregation is often quantified in terms of a familial relative risk (FRR), and although at first glance this measure may seem simple and intuitive as an average risk prediction, its implications are not straightforward., Methods: We use two statistical models for the distribution of disease risk in a population: a dichotomous risk model that gives an intuitive understanding of the implication of a given FRR, and a continuous risk model that facilitates a more detailed computation of the inequalities in disease risk. Published estimates of FRRs are used to produce Lorenz curves and Gini indices that quantifies the inequalities in risk for a range of diseases., Results: We demonstrate that even a moderate familial association in disease risk implies a very large difference in risk between individuals in the population. We give examples of diseases for which this is likely to be true, and we further demonstrate the relationship between the point estimates of FRRs and the distribution of risk in the population., Conclusions: The variation in risk for several severe diseases may be larger than the variation in income in many countries. The implications of familial risk estimates should be recognized by epidemiologists and clinicians.

Objectives: Surgical resection is the recommended treatment for patients with early-stage non-small-cell lung cancer. However, it is believed that causes other than lung cancer can lead to death following surgical resection. Investigating the risk factors for overall mortality and analysing the specific causes of death may indicate the degree of influence of other causes of death., Methods: We assessed individual risk factors affecting overall and cause-specific mortality in a Cox proportional hazards model in a cohort of patients with resected Stage I/II non-small-cell lung cancer (n = 756) from 2007 to 2015 in a tertiary university centre. The follow-up period ranged from 3 days to 9.3 years. Median survival time was 7.3 years (95% confidence interval 6.0-7.9). A few patients died of cardiovascular disease (n = 19) and were included in the group 'other cause'. In a competing risk model, we evaluated the risk factors for specific causes of death in patients dying of lung cancer and dying of non-lung cancer specific conditions., Results: The overall survival was 94%, 62% and 50% at 1, 5 and 7 years, respectively. At the end of the follow-up period, the risk of having died of, respectively, lung cancer or other causes was 36% and 24%. The cumulative incidence of death of lung cancer increased continuously during the study. Risk factors predicting death of all causes and death of non-small-cell lung cancer were increasing age, severely reduced lung function, Eastern Cooperative Oncology Group Performance Status ≥2, preoperative examination without positron emission tomography/computed tomography, histological tumour diagnosis other than adenocarcinoma and squamous cell carcinoma and increasing disease stage. In patients dying of other causes, age, gender, body mass index, smoking and Eastern Cooperative Oncology Group Performance Status ≥2 affected the mortality rate., Conclusions: The probability of having died of lung cancer continued to increase beyond 5 years after the operation. Surveillance of risk factors associated with an increased mortality rate should be considered in the postoperative follow-up examination after lung cancer resection., (© The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Heritability is often estimated by decomposing the variance of a trait into genetic and other factors. Interpreting such variance decompositions, however, is not straightforward. In particular, there is an ongoing debate on the importance of genetic factors in cancer development, even though heritability estimates exist. Here we show that heritability estimates contain information on the distribution of absolute risk due to genetic differences. The approach relies on the assumptions underlying the conventional heritability of liability model. We also suggest a model unrelated to heritability estimates. By applying these strategies, we describe the distribution of absolute genetic risk for 15 common cancers. We highlight the considerable inequality in genetic risk of cancer using different metrics, e.g., the Gini Index and quantile ratios which are frequently used in economics. For all these cancers, the estimated inequality in genetic risk is larger than the inequality in income in the USA.

After the introduction of the prostate specific antigen (PSA) test in the 1980s, a sharp increase in the incidence rate of prostate cancer was seen in the United States. The age-specific incidence patterns exhibited remarkable shifts to younger ages, and declining rates were observed at old ages. Similar trends were seen in Norway. We investigate whether these features could, in combination with PSA testing, be explained by a varying degree of susceptibility to prostate cancer in the populations. We analyzed incidence data from the United States' Surveillance, Epidemiology, and End Results program for 1973-2010, comprising 511,027 prostate cancers in men ≥40 years old, and Norwegian national incidence data for 1953-2011, comprising 113,837 prostate cancers in men ≥50 years old. We developed a frailty model where only a proportion of the population could develop prostate cancer, and where the increased risk of diagnosis due to the massive use of PSA testing was modelled by encompassing this heterogeneity in risk. The frailty model fits the observed data well, and captures the changing age-specific incidence patterns across birth cohorts. The susceptible proportion of men is [Formula: see text] in the United States and [Formula: see text] in Norway. Cumulative incidence rates at old age are unchanged across birth cohort exposed to PSA testing at younger and younger ages. The peaking cohort-specific age-incidence curves of prostate cancer may be explained by the underlying heterogeneity in prostate cancer risk. The introduction of the PSA test has led to a larger number of diagnosed men. However, no more cases are being diagnosed in total in birth cohorts exposed to the PSA era at younger and younger ages, even though they are diagnosed at younger ages. Together with the earlier peak in the age-incidence curves for younger cohorts, and the strong familial association of the cancer, this constitutes convincing evidence that the PSA test has led to a higher proportion, and an earlier timing, of diagnoses in a limited pool of susceptible individuals.

Counter-intuitive associations appear frequently in epidemiology, and these results are often debated. In particular, several scenarios are characterized by a general risk factor that appears protective in particular subpopulations, for example, individuals suffering from a specific disease. However, the associations are not necessarily representing causal effects. Selection bias due to conditioning on a collider may often be involved, and causal graphs are widely used to highlight such biases. These graphs, however, are qualitative, and they do not provide information on the real life relevance of a spurious association. Quantitative estimates of such associations can be obtained from simple statistical models. In this study, we present several paradoxical associations that occur in epidemiology, and we explore these associations in a causal, frailty framework. By using frailty models, we are able to put numbers on spurious effects that often are neglected in epidemiology. We discuss several counter-intuitive findings that have been reported in real life analyses, and we present calculations that may expand the understanding of these associations. In particular, we derive novel expressions to explain the magnitude of bias in index-event studies.

The role of randomness, environment and genetics in cancer development is debated. We approach the discussion by using the potential outcomes framework for causal inference. By briefly considering the underlying assumptions, we suggest that the antagonising views arise due to estimation of substantially different causal effects. These effects may be hard to interpret, and the results cannot be immediately compared. Indeed, it is not clear whether it is possible to define a causal effect of chance at all., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Frailty models are here proposed in the tumor dormancy framework, in order to account for possible unobservable dependence mechanisms in cancer studies where a non-negligible proportion of cancer patients relapses years or decades after surgical removal of the primary tumor. Relapses do not seem to follow a memory-less process, since their timing distribution leads to multimodal hazards. From a biomedical perspective, this behavior may be explained by tumor dormancy, i.e., for some patients microscopic tumor foci may remain asymptomatic for a prolonged time interval and, when they escape from dormancy, micrometastatic growth results in a clinical disease appearance. The activation of the growth phase at different metastatic states would explain the occurrence of metastatic recurrences and mortality at different times (multimodal hazard). We propose a new frailty model which includes in the risk function a random source of heterogeneity (frailty variable) affecting the components of the hazard function. Thus, the individual hazard rate results as the product of a random frailty variable and the sum of basic hazard rates. In tumor dormancy, the basic hazard rates correspond to micrometastatic developments starting from different initial states. The frailty variable represents the heterogeneity among patients with respect to relapse, which might be related to unknown mechanisms that regulate tumor dormancy. We use our model to estimate the overall survival in a large breast cancer dataset, showing how this improves the understanding of the underlying biological process., (© 2016, The International Biometric Society.)

The concept of frailty plays a major role in the statistical field of survival analysis. Frailty variation refers to differences in risk between individuals which go beyond known or measured risk factors. In other words, frailty variation is unobserved heterogeneity. Although understanding frailty is of interest in its own right, the literature on survival analysis has demonstrated that existence of frailty variation can lead to surprising artefacts in statistical estimation that are important to examine. We present literature that demonstrates the presence and significance of frailty variation between individuals. We discuss the practical content of frailty variation, and show the link between frailty and biological concepts like (epi)genetics and heterogeneity in disease risk. There are numerous suggestions in the literature that a good deal of this variation may be due to randomness, in addition to genetic and/or environmental factors. Heterogeneity often manifests itself as clustering of cases in families more than would be expected by chance. We emphasize that apparently moderate familial relative risks can only be explained by strong underlying variation in disease risk between families and individuals. Finally, we highlight the potential impact of frailty variation in the interpretation of standard epidemiological measures such as hazard and incidence rates., (© The Author 2014. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Using a 2-level hierarchical frailty model, we analyzed population-wide data on testicular germ-cell tumor (TGCT) status in 1,135,320 two-generational Norwegian families to examine the risk of TGCT in family members of patients. Follow-up extended from 1954 (cases) or 1960 (unaffected persons) to 2008. The first-level frailty variable was compound Poisson-distributed. The underlying Poisson parameter was randomized to model the frailty variation between families and was decomposed additively to characterize the correlation structure within a family. The frailty relative risk (FRR) for a son, given a diseased father, was 4.03 (95% confidence interval (CI): 3.12, 5.19), with a borderline significantly higher FRR for nonseminoma than for seminoma (P = 0.06). Given 1 affected brother, the lifetime FRR was 5.88 (95% CI: 4.70, 7.36), with no difference between subtypes. Given 2 affected brothers, the FRR was 21.71 (95% CI: 8.93, 52.76). These estimates decreased with the number of additional healthy brothers. The estimated FRRs support previous findings. However, the present hierarchical frailty approach allows for a very precise definition of familial risk. These FRRs, estimated according to numbers of affected/nonaffected family members, provide new insight into familial TGCT. Furthermore, new light is shed on the different familial risks of seminoma and nonseminoma.

The Armitage-Doll model with random frailty can fail to describe incidence rates of rare cancers influenced by an accelerated biological mechanism at some, possibly short, period of life. We propose a new model to account for this influence. Osteosarcoma and Ewing sarcoma are primary bone cancers with characteristic age-incidence patterns that peak in adolescence. We analyze Surveillance, Epidemiology and End Result program incidence data for whites younger than 40 years diagnosed during the period 1975-2005, with an Armitage-Doll model with compound Poisson frailty. A new model treating the adolescent growth spurt as the accelerated mechanism affecting cancer development is a significant improvement over that model. We also model the incidence rate conditioning on the event of having developed the cancers before the age of 40 years and compare the results with those predicted by the Armitage-Doll model. Our results support existing evidence of an underlying susceptibility for the two cancers among a very small proportion of the population. In addition, the modeling results suggest that susceptible individuals with a rapid growth spurt acquire the cancers sooner than they otherwise would have if their growth had been slower. The new model is suitable for modeling incidence rates of rare diseases influenced by an accelerated biological mechanism., (Copyright © 2012 John Wiley & Sons, Ltd.)