Search

This paper provides guidance for researchers with some mathematical background on the conduct of time-to-event analysis in observational studies based on intensity (hazard) models. Discussions of basic concepts like time axis, event definition and censoring are given. Hazard models are introduced, with special emphasis on the Cox proportional hazards regression model. We provide check lists that may be useful both when fitting the model and assessing its goodness of fit and when interpreting the results. Special attention is paid to how to avoid problems with immortal time bias by introducing time-dependent covariates. We discuss prediction based on hazard models and difficulties when attempting to draw proper causal conclusions from such models. Finally, we present a series of examples where the methods and check lists are exemplified. Computational details and implementation using the freely available R software are documented in Supplementary Material. The paper was prepared as part of the STRATOS initiative. [ABSTRACT FROM AUTHOR]

Objective: To examine how childhood weight trajectories are associated with disordered eating behaviours (DEBs) in early adolescence. Methods: Self‐reports on DEBs (fasting, purging, and binge eating) were obtained from 18,337 children in the 11‐year follow‐up of the Danish National Birth Cohort. For this population, birth register information on gestational age and birth weight was categorized into the following: small, appropriate, and large for gestational age. Prospective parent‐reported height and weight data at child ages 1 and 7 years were dichotomized using standardized cut‐offs into non‐overweight and overweight. A 12‐category weight trajectory variable was created, and the associations between weight trajectory and DEBs were estimated using logistic regression. Results: In total, 7.0% 11‐ to 12‐year olds reported DEBs. Compared with children born appropriate for gestational age and being non‐overweight at age 1 and 7 years, children born small for gestational age and who were overweight at age 1 and 7 years had a very high risk of disordered eating (OR 7.00; CI [2.57, 19.40]). The statistical analyses revealed, however, that overweight at age 7 years was the main contributor and independently of trajectory increased the risk of disordered eating at age 11–12 years significantly (OR 3.16 CI [2.73, 3.65]). Conclusion: Overweight not in the first year of life, but at age 7 years was more predictive for DEBs. [ABSTRACT FROM AUTHOR]

Background: Socioeconomic inequalities in birth weight and in body mass index (BMI) later in childhood are in opposite directions, which raises questions about when during childhood the change in direction happens. We examined how maternal and paternal education and household income were associated with birthweight z-scores and with BMI z-scores at age 5 and 12 months and 7 years, and we examined the socioeconomic differences in the tracking of these z-scores across infancy and childhood. Methods: The associations were studied in a cohort of children in the Danish National Birth Cohort, single born between 1997 and 2003, for whom information on body size from at least 1 of 4 time points (n=85 062) was recorded. We examined the associations using linear mixed-effects modelling. Results: Children from families with a low maternal and paternal educational level changed their body size z-scores upwards between birth and age 7 years. At age 5 and 12 months, there were no educational gradient. A low maternal educational level was associated with lower birth weight for gestational age z-scores at birth for boys (-0.199; 95% CI -0.230 to -0.169) and girls (-0.198; 95% CI -0.229 to -0.167) and higher BMI z-scores at age 7 for boys (0.198; 95% CI 0.154 to 0.242) and girls (0.218; 95% CI 0.173 to 0.264). There was not a similarly clear pattern in the tracking between different household income groups. However, a low household income level was associated with higher z-scores of both birth weight and BMI at age 7 years, but with a much weaker gradient at 5 and 12 months. Conclusions: The educational gradient shifts from positive with birth weight, to none during infancy to inverse with BMI at age 7 years. In contrast, the income gradient was positive at birth and at 7 years and much weaker during infancy. [ABSTRACT FROM AUTHOR]

Objectives: Although well established, the association between socioeconomic position and health and health behaviour is not clearly understood, and it has been speculated that familial factors, for example, dispositional factors or exposures in the rearing environment, may be underlying the association. The objective was to compare prescription fillings within twin pairs who are partly or fully genetically identical and share childhood exposures. Design: Twin cohort study. Setting: Denmark. Participants: Data from the Danish Twin Registry were linked to registers in Statistics Denmark and the Danish Registry of Medicinal Product statistics. A total of 8582 monozygotic (MZ) and 15 788 dizygotic same sex (DZSS) twins were included. Outcome measures: Number of prescription fillings during follow-up (1995-2005) was analysed according to education and income. Results of unpaired and intrapair analyses were compared. Results: An inverse social gradient in filling of prescriptions for all-purpose and system-specific drugs was observed in the unpaired analyses. In the intrapair analyses, associations were attenuated some in DZSS and more in MZ twins. Filling of drugs targeting the nervous system was still strongly associated with income in the intrapair analyses. Conclusions: Familial factors seem to account for part of the observed social inequality in filling of prescription medicine. [ABSTRACT FROM AUTHOR]

Juhl M, Strandberg-Larsen K, Larsen PS, Andersen PK, Svendsen SW, Bonde JP, Nybo Andersen A-M. Occupational lifting during pregnancy and risk of fetal death In a large national cohort study. Scand J Work Environ Health. 2013;39(4):335-342. doi:10.5271/sjweh.3335 Objective The aim of the present study was to examine the association between occupational lifting and the risk of fetal death according to gestational age Methods We used data from the Danish National Birth Cohort (1996-2002). Among 71 500 occupational active women, 2886 experienced a fetal death. Information on lifting and relevant covariates was collected in interviews around week 16 of pregnancy. The majority of fetal losses (N=2032) happened before the scheduled interview, and exposure data were collected retrospectively from these women. We analyzed early miscarriage (<12 weeks), late miscarriage (13-21 weeks), and stillbirth (>22 weeks), using Cox-regression models with gestational age as the underlying time variable. Results The adjusted early miscarriage risk increased with frequency of daily lifts and total burden lifted per day. For example, the hazard ratio was 1.38 [95% confidence interval (95% CI) 1.10-1.74] for a total weight load per day of 101-200 kg and 2.02 (95% CI 1.23-3.33) for a daily load >1000 kg as compared to non-lifters (P for trend <0.0001). Late miscarriage was associated with total daily weight load (P for trend=0.0073) but not with number of lifts per day. There was no association between occupational lifting and stillbirth. Conclusions In the present study, the risk of miscarriage increased with the number of lifts and total burden lifted per day at work. There may be a case for advising pregnant women against heavy lifting in particular dur-ing early pregnancy. [ABSTRACT FROM AUTHOR]

This paper presents a study of the mortality of insulin-dependent diabetics diagnosed before age 31. The analysis includes the effect of various covariates on the mortality and on the risk of developing diabetic nephropathy, a serious renal complication associated with diabetes. The results show that it is the risk of developing nephropathy combined with very high mortality rates of patients with nephropathy which are the main reasons for the excess mortality usually experienced among insulin-dependent diabetics. The results are used to provide examples of the cost of individual life and group life insurance for diabetics who, at the time of issue of insurance, show no sign of diabetic nephropathy. [ABSTRACT FROM PUBLISHER]

A response to a letter to the editor is presented on an article about the relationship between lithium response and the timing of treatment in patients with bipolar disorder, which appeared in the previous issue.

Summary Background: Infection with certain types of human papillomavirus (HPV), which is common among young women, increases the risk of cervical cancer. However, less than 1% of young women positive for oncogenic types of HPV develop cervical cancer. We investigated whether the amount of HPV DNA is a useful predictor of progression to cervical carcinoma in situ.Methods: We estimated the amount of HPV 16 DNA by a PCR that uses the 59-exonuclease (Taqman) method, in 478 women with cervical carcinoma in situ and 608 individually matched controls. To adjust for differences in the amount of genomic DNA between samples, we estimated the amount of a nuclear gene ([BETA]-actin). We studied multiple smears (total 3835 archived samples) from each woman, taken over periods of up to 26 years, that covered normal cytology to development of cervical cancer.Findings: The risk of cervical carcinoma in situ increased with the amount of HPV 16 DNA. Analysis of the first smear from each woman, collected a mean of 7.8 years before cancer diagnosis, showed that women with the 20% highest amount of HPV 16 DNA were at a 60-fold higher risk of developing cervical carcinoma in situ than women negative for HPV 16. The first smear samples were classified as normal by squamous-cell cytology.Interpretation: Analysis of the amount of HPV DNA can predict cancer risk at a stage when current screening methods are uninformative. Testing for the amount of HPV 16 DNA during gynaecological health checks might strikingly improve our ability to distinguish between infections that have a high or low risk of progressing into cervical cancer. [ABSTRACT FROM AUTHOR]

SummaryBackground: Persistent infection with certain types of human papillomavirus (HPV) is believed to be a prerequisite for the development of cervical neoplasia. Persistence may depend on certain characteristics, such as viral load, which has so far been given little attention. We investigated the association between HPV 16 viral load and cervical carcinoma in situ.Methods: We did a nested case-control study of women participating in cytological screening in Sweden. We used a sensitive quantitative PCR assay to estimate HPV 16 load in multiple smears for each woman, taken during a period of up to 26 years before diagnosis. We calculated C[sub t] values, which decrease as the number of viral DNA copies increases.Findings: 2081 smears from 478 cases and 1754 smears from 608 controls were tested. Among cases, we found a consistently increased load of HPV 16 already 13 years or more before diagnosis, and when many smears were still cytologically normal. Women with high HPV 16 viral loads were at least 30 times the relative risk of HPV-16-negative women more than a decade before diagnosis. The increase in relative risk was constant over time. About 25% of women (95% CI 0.12-0.32) infected with a high viral load before age 25 years developed cervical carcinoma in situ within 15 years.Interpretation: Cervical carcinoma in situ associated with HPV 16 occurs mainly in HPV-16-positive women who have consistently high viral loads long term. Women at high risk could be identified by use of a quantitative HPV test in addition to cytological screening. [ABSTRACT FROM AUTHOR]

Aim: The latest guidelines from ACC/AHA define hypertension at systolic blood pressure (SBP) 130-139 mmHg or diastolic blood pressure (DBP) 80-89 mmHg in contrast to guidelines from ESC/ESH defining hypertension at SBP ≥ 140 mmHg or DBP ≥ 90 mmHg. The aim was to determine whether the ACC/AHA definition of hypertension identifies persons at elevated risk for future cardiovascular outcome., Methods: In a Danish prospective cardiovascular study, 19,721 white men and women aged 20-98 years were examined up to five occasions between 1976 and 2015. The population was followed until December 2018. The ACC/AHA definition of the BP levels were applied: Normal: SBP <120 mmHg and DBP <80 mmHg, Elevated: SBP 120-129 mmHg and DBP <80 mmHg, Stage 1: SBP 130-139 mmHg or DBP 80-89 mmHg, Stage 2: SBP ≥140 mmHg or DBP ≥90 mmHg. Absolute 10-year risk was calculated taking repeated examinations, covariates, and competing risk into account., Results: For all outcomes, the 10-year risk in stage 1 hypertension did not differ significantly from risk in subjects with normal BP: The 10-year risk of cardiovascular events in stage 1 hypertension was 14.1% [95% CI 13.2;15.0] and did not differ significantly from the risk in normal BP at 12.8% [95% CI 11.1;14.5] ( p  = 0.19). The risk was highest in stage 2 hypertension 19.4% [95% CI 18.9;20.0] and differed significantly from normal BP, elevated BP, and stage 1 hypertension ( p  < 0.001). The 10-year risk of cardiovascular death was 6.6% [95% CI 5.9;7.4] in stage 1 hypertension and did not differ significantly from the risk in normal BP at 5.7% [95% CI 4.1;7.3] ( p  = 0.33)., Conclusions: Stage 1 hypertension as defined by the ACC/AHA guidelines has the same risk for future cardiovascular events as normal BP. In contrast, the definition of hypertension as suggested by ESC/ESH identifies patients with elevated risk of cardiovascular events.

Importance: More than 30 million people live with a stroke diagnosis worldwide. Depression after stroke is frequent, and greater knowledge of associated risk factors and outcomes is needed to understand the etiology and implications of this disabling complication., Objectives: To examine whether the incidence of and risk factors for depression differ between patients with stroke and a reference population without stroke and to assess how depression influences mortality., Design, Setting, and Participants: Register-based cohort study in Denmark. Participants were all individuals 15 years or older with a first-time hospitalization for stroke between January 1, 2001, and December 31, 2011 (n = 157 243), and a reference population (n = 160 236) matched on age, sex, and municipality. The data were analyzed between January and March 2016., Main Outcomes and Measures: The incidence of depression and mortality outcomes of depression (defined by hospital discharge diagnoses or antidepressant medication use) were examined using Cox proportional hazards regression analyses., Results: In total, 34 346 patients (25.4%) with stroke and 11 330 (7.8%) in the reference population experienced depression within 2 years after study entry. Compared with the reference population, patients with stroke had a higher incidence of depression during the first 3 months after hospitalization (hazard ratio for stroke vs the reference population, 8.99; 95% CI, 8.61-9.39), which declined during the second year of follow-up (hazard ratio for stroke vs the reference population, 1.93; 95% CI, 1.85-2.08). Significant risk factors for depression for patients with stroke and the reference population included older age, female sex, single cohabitation status, basic educational attainment, diabetes, high level of somatic comorbidity, history of depression, and stroke severity (in patients with stroke). The associations were strongest for the reference population. In both populations, depressed individuals, especially those with new onset, had increased all-cause mortality (hazard ratio for new-onset depression, 1.89 [95% CI, 1.83-1.95] for patients with stroke and 3.75 [95% CI, 3.51-4.00] for the reference population) after adjustment for confounders. Similar patterns were found for natural and unnatural causes of death. In most models, the depression-related relative mortality was approximately twice as high in the reference population vs the stroke population., Conclusions and Relevance: Depression is common in patients with stroke during the first year after diagnosis, and those with prior depression or severe stroke are especially at risk. Because a large number of deaths can be attributable to depression after stroke, clinicians should be aware of this risk.

Objectives: To investigate the role of factors that modulate the association between alcohol and mortality, and to provide estimates of absolute risk of death., Design: The European Prospective Investigation into Cancer and nutrition (EPIC)., Setting: 23 centres in 10 countries., Participants: 380 395 men and women, free of cancer, diabetes, heart attack or stroke at enrolment, followed up for 12.6 years on average., Main Outcome Measures: 20 453 fatal events, of which 2053 alcohol-related cancers (ARC, including cancers of upper aerodigestive tract, liver, colorectal and female breast), 4187 cardiovascular diseases/coronary heart disease (CVD/CHD), 856 violent deaths and injuries. Lifetime alcohol use was assessed at recruitment., Results: HRs comparing extreme drinkers (≥30 g/day in women and ≥60 g/day in men) to moderate drinkers (0.1-4.9 g/day) were 1.27 (95% CI 1.13 to 1.43) in women and 1.53 (1.39 to 1.68) in men. Strong associations were observed for ARC mortality, in men particularly, and for violent deaths and injuries, in men only. No associations were observed for CVD/CHD mortality among drinkers, whereby HRs were higher in never compared to moderate drinkers. Overall mortality seemed to be more strongly related to beer than wine use, particularly in men. The 10-year risks of overall death for women aged 60 years, drinking more than 30 g/day was 5% and 7%, for never and current smokers, respectively. Corresponding figures in men consuming more than 60 g/day were 11% and 18%, in never and current smokers, respectively. In competing risks analyses, mortality due to CVD/CHD was more pronounced than ARC in men, while CVD/CHD and ARC mortality were of similar magnitude in women., Conclusions: In this large European cohort, alcohol use was positively associated with overall mortality, ARC and violent death and injuries, but marginally to CVD/CHD. Absolute risks of death observed in EPIC suggest that alcohol is an important determinant of total mortality., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)