Evaluating mammography screening in observational cohort designs: the importance of avoiding lead time bias.

AIMS: To investigate the potential lead time bias of the evaluation model (extended follow-up for women diagnosed with breast cancer) used to evaluate mammography screening in a recent Danish study. This model was compared with two traditional models. METHODS: We retrieved data on women diagnosed with breast cancer in each county of Norway from 1986 to 2016. In a population-based open cohort study, the change in incidence-based mortality (IBM) was estimated by relative rate ratios comparing a screening period with a historical period for each of three age groups: women eligible for screening and younger and older ineligible women. We applied the evaluation model, and for comparison two traditional IBM models from a recent Norwegian study: one without extended follow-up and no possibility of lead time bias and one with extended follow-up irrespective of diagnosis, possibly diluting any screening effect. RESULTS: The evaluation model estimated an extra 11% reduction in breast cancer mortality among the screening eligible relative to ineligible women. However, this result could largely be ascribed to lead time bias inflated by overdiagnosis and a decreasing mortality from other causes among eligible women. A reduction in breast cancer mortality was observed for both eligible and younger and older ineligible women across models, and relative rate ratios close to 1 were obtained using the two traditional IBM models, indicating no effect of screening on breast cancer mortality. CONCLUSIONS: Two models without lead time bias found no reduction in breast cancer mortality, whereas the evaluation model estimated a reduction attributable to lead time bias.

Patients with repeated acute admissions to somatic departments: sociodemographic characteristics, disease burden, and contact with primary healthcare sector - a retrospective register-based case-control study.

BACKGROUND: Healthcare systems face escalating capacity challenges and patients with repeated acute admissions strain hospital resources disproportionately. However, studies investigating the characteristics of such patients across all public healthcare providers in a universal healthcare system are lacking. OBJECTIVE: To investigate characteristics of patients with repeated acute admissions (three or more acute admissions within a calendar year) in regard to sociodemographic characteristics, disease burden, and contact with the primary healthcare sector. METHODS: This matched register-based case-control study investigated repeated acute admissions from 1 January 2014 to 31 December 2018, among individuals, who resided in four Danish municipalities. The study included 6169 individuals with repeated acute admissions, matched 1:4 to individuals with no acute admissions and one to two acute admissions, respectively. Group comparisons were conducted using conditional logistic regression. RESULTS: Receiving social benefits increased the odds of repeated acute admissions 9.5-fold compared with no acute admissions (odds ratio (OR) 9.5; 95% confidence interval (CI) 8.5; 10.6) and 3.4-fold compared with one to two acute admissions (OR 3.4; 95% CI 3.1; 3.7). The odds of repeated acute admissions increased with the number of used medications and chronic diseases. Having a mental illness increased the odds of repeated acute admissions 5.8-fold when compared with no acute admissions (OR 5.7; 95% CI 5.2; 6.4) and 2.3-fold compared with one to two acute admissions (OR 2.3; 95% CI 2.1; 2.5). Also, high use of primary sector services (e.g. nursing care) increased the odds of repeated acute admissions when compared with no acute admissions and one to two acute admissions. CONCLUSIONS: This study pinpointed key factors encompassing social status, disease burden, and healthcare utilisation as pivotal markers of risk for repeated acute admissions, thus identifying high-risk patients and facilitating targeted intervention.

Impact of low-dose quetiapine-use on glycosylated hemoglobin, triglyceride and cholesterol levels.

OBJECTIVE: Quetiapine use at standard doses has been associated with hyperglycemia and dyslipidemia. However, whether even frequently prescribed low-dose quetiapine results in significant metabolic disturbances remains unclear. Thus, this study aimed to investigate the association between off-label, low-dose quetiapine and changes in glycosylated hemoglobin (HbA1c) levels/lipid parameters. METHODS: We identified new users of low-dose quetiapine (≤50 mg tablets) in Denmark 2008-2018 with measurements of HbA1c, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), or fasting triglycerides (fTG) within 365 days before and after quetiapine initiation. Mixed-effects linear regression models were used to estimate coefficients (ß) with 95% confidence intervals (95%CIs) for change in cardiometabolic parameters after quetiapine initiation. Inverse probability weighting was used to mitigate selection bias. Higher doses of quetiapine (>50 mg) were included in sensitivity analyses. RESULTS: Among 106,711 eligible new low-dose quetiapine users (median age = 45 years, females = 55%), low-dose quetiapine initiation was associated with increased fTG (ß = 1.049[95%CI:1.027-1.072]) and decreased HDL-C (ß = 0.982[0.978-0.986]). Although HbA1c did not change significantly and TC and LDL-C even decreased considering all subjects, all three metabolic parameters increased significantly among individuals with normal pre-quetiapine initiation levels. The adverse metabolic effect of quetiapine on HbA1c, TC, LDL-C, and HDL-C was dose-dependent, which was not the case for fTG. CONCLUSIONS: Low-dose quetiapine was associated with a significant increase in fTG and decreases in HDL-C in all subjects, as well as with significant increases in HbA1c, TC, and LDL-C among those with normal baseline values. The risk of metabolic worsening with quetiapine was dose-dependent, except for fTG.

Colon cancer diagnosed in patients with non-specific symptoms - comparisons between diagnostic paradigms.

Background In Denmark, the Cancer Patient Pathway for Non-Specific Signs and Symptoms (NSSC-CPP) has been implemented with variations: in some areas, general practitioners (GPs) do the initial diagnostic work-up (GP paradigm); in other areas, patients are referred directly to the hospital (hospital paradigm). There is no evidence to suggest the most beneficial organisation. Therefore, this study aims to compare the occurrence of colon cancer and the risk of non-localised cancer stage between the GP and hospital paradigms.Material and Methods In this registry-based case-control study, we applied multivariable binary logistic regression models to estimate the odds ratios (OR) of colon cancer and non-localised stage associated with the GP paradigm and hospital paradigm. All cases and controls were assigned to a paradigm based on their diagnostic activity (CT scan or CPP) six months before the index date. As not all CT scans in the control group were part of the cancer work-up as a sensitivity analysis, we investigated the impact of varying the fraction of these, which were randomly removed using a bootstrap approach for inference.Results The GP paradigm was more likely to result in a cancer diagnosis than the hospital paradigm; ORs ranged from 1.91-3.15 considering different fractions of CT scans as part of cancer work-up. No difference was found in the cancer stage between the two paradigms; ORs ranged from 1.08-1.10 and were not statistically significant.Conclusion Patients in the GP paradigm were diagnosed with colon cancer more often, but we cannot conclude that the distribution of respectively localised or non-localised extent of disease is different from that of patients in the hospital paradigm.

Women's health literacy and attendance in breast cancer screening: a Danish population-based study combining survey and register data.

AIM: To investigate the association between women's health literacy and attendance in the Danish national breast cancer screening programme. METHODS: In a population-based cross-sectional study, information on two health literacy subscales, measured using the Health Literacy Questionnaire (HLQ), and sociodemographic factors was obtained from the 'How are you? 2017' survey in the Central Denmark Region. Information on screening attendance was obtained from register data from 2016-2017. Data were linked based on individual civil registration numbers. To account for missing data, multiple imputation by chained equations was implemented to fill in missing values on all variables. Unadjusted and adjusted logistic regression analyses were performed separately for two HLQ subscales to estimate odds ratio (OR) of screening attendance. Both multiple imputation analyses and complete case analyses were performed. RESULTS: A total of 6012 women were included in multiple imputed statistical analyses. Generally, women had high health literacy levels. In multiple imputed analyses, the unadjusted OR of the primary HLQ subscale, understanding, was 1.32 (95% confidence interval (CI): 1.10-1.59), indicating higher odds for screening attendance with higher health literacy level. However, after adjustment no significant association between the HLQ subscale of understanding and screening attendance was found (OR 1.09 (95% CI: 0.90-1.33)). Similar results were found for the secondary HLQ subscale of engaging (insignificant association in adjusted analysis). No effect modification from sociodemographic characteristics was found. Similar results were found in complete case analyses. CONCLUSIONS: No significant association was found between health literacy and attendance in the Danish breast cancer screening programme.

Changing characteristics over time of individuals receiving COVID-19 vaccines in Denmark: A population-based descriptive study of vaccine uptake.

AIMS: The Danish authorities implemented a differential rollout of the COVID-19 vaccines where individuals at high risk of COVID-19 were prioritized. We describe the temporal uptake and characteristics of COVID-19 vaccine recipients in Denmark. METHODS: Using nationwide healthcare registries, we identified all Danish residents ⩾5 years of age who received at least one dose of a COVID-19 vaccine from 27 December 2020-29 January 2022. We charted the daily number of newly vaccinated individuals and the cumulative vaccine coverage over time, stratified by vaccine type, age groups and vaccination priority groups, and described characteristics of vaccine recipients during two-month-intervals and in vaccination priority groups. RESULTS: By 29 January 2022, 88%, 86% and 64% of Danish residents ⩾5 years (n=5,562,008) had received a first, second and third dose, respectively, of a COVID-19 vaccine, most commonly the BNT162b2 vaccine (84%). Uptake ranged from 48% in 5-11-year-olds to 98% in 65-74-year-olds. Individuals vaccinated before June 2021 were older (median age 61-70 years vs 10-35 years in later periods) and had more comorbidities such as hypertension (22-28% vs 0.77-2.8% in later periods), chronic lung disease (9.4-15% vs 3.7-4.6% in later periods) and diabetes (9.3-12% vs 0.91-2.4% in later periods). CONCLUSIONS: We document substantial changes over time in, for example, age, sex and medical history of COVID-19 vaccine recipients. Though these results are related to the differential vaccine rollout in Denmark, similar findings are probable in other countries and should be considered when designing and interpreting studies on the effectiveness and safety of COVID-19 vaccines.

Change in effectiveness of mammography screening with decreasing breast cancer mortality: a population-based study.

BACKGROUND: Reductions in breast cancer mortality observed over the last three decades are partly due to improved patient management, which may erode the benefit-harm balance of mammography screening. METHODS: We estimated the numbers of women needed to invite (NNI) to prevent one breast cancer death within 10 years. Four scenarios of screening effectiveness (5-20% mortality reduction) were applied on 10,580 breast cancer deaths among Norwegian women aged 50-75 years from 1986 to 2016. We used three scenarios of overdiagnosis (10-40% excess breast cancers during screening period) for estimating ratios of numbers of overdiagnosed breast cancers for each breast cancer death prevented. RESULTS: Under the base case scenario of 20% breast cancer mortality reduction and 20% overdiagnosis, the NNI rose from 731 (95% CI: 644-830) women in 1996 to 1364 (95% CI: 1181-1577) women in 2016, while the number of women with overdiagnosed cancer for each breast cancer death prevented rose from 3.2 in 1996 to 5.4 in 2016. For a mortality reduction of 8.7%, the ratio of overdiagnosed breast cancers per breast cancer death prevented rose from 7.4 in 1996 to 14.0 in 2016. For a mortality reduction of 5%, the ratio rose from 12.8 in 1996 to 25.2 in 2016. CONCLUSIONS: Due to increasingly potent therapeutic modalities, the benefit in terms of reduced breast cancer mortality declines while the harms, including overdiagnosis, are unaffected. Future improvements in breast cancer patient management will further deteriorate the benefit-harm ratio of screening.

Maternal weight change from prepregnancy to 18 months postpartum and subsequent risk of hypertension and cardiovascular disease in Danish women: A cohort study.

BACKGROUND: One-fourth of women experience substantially higher weight years after childbirth. We examined weight change from prepregnancy to 18 months postpartum according to subsequent maternal risk of hypertension and cardiovascular disease (CVD). METHODS AND FINDINGS: We conducted a cohort study of 47,966 women with a live-born singleton within the Danish National Birth Cohort (DNBC; 1997-2002). Interviews during pregnancy and 6 and 18 months postpartum provided information on height, gestational weight gain (GWG), postpartum weights, and maternal characteristics. Information on pregnancy complications, incident hypertension, and CVD was obtained from the National Patient Register. Using Cox regression, we estimated adjusted hazard ratios (HRs; 95% confidence interval [CI]) for hypertension and CVD through 16 years of follow-up. During this period, 2,011 women were diagnosed at the hospital with hypertension and 1,321 with CVD. The women were on average 32.3 years old (range 18.0-49.2) at start of follow-up, 73% had a prepregnancy BMI <25, and 27% a prepregnancy BMI ≥25. Compared with a stable weight (±1 BMI unit), weight gains from prepregnancy to 18 months postpartum of >1-2 and >2 BMI units were associated with 25% (10%-42%), P = 0.001 and 31% (14%-52%), P < 0.001 higher risks of hypertension, respectively. These risks were similar whether weight gain presented postpartum weight retention or a new gain from 6 months to 18 months postpartum and whether GWG was below, within, or above the recommendations. For CVD, findings differed according to prepregnancy BMI. In women with normal-/underweight, weight gain >2 BMI units and weight loss >1 BMI unit were associated with 48% (17%-87%), P = 0.001 and 28% (6%-55%), P = 0.01 higher risks of CVD, respectively. Further, weight loss >1 BMI unit combined with a GWG below recommended was associated with a 70% (24%-135%), P = 0.001 higher risk of CVD. No such increased risks were observed among women with overweight/obesity (interaction by prepregnancy BMI, P = 0.01, 0.03, and 0.03, respectively). The limitations of this observational study include potential confounding by prepregnancy metabolic health and self-reported maternal weights, which may lead to some misclassification. CONCLUSIONS: Postpartum weight retention/new gain in all mothers and postpartum weight loss in mothers with normal-/underweight may be associated with later adverse cardiovascular health.

A new likelihood model for analyses of pharmacoepidemiologic case-control studies which avoids decision rules for determining latent exposure status.

BACKGROUND: Case-control studies based on pharmaco-epidemiological databases typically use decision rules to determine exposure status from information on dates of prescription redemptions, although this induces misclassification. The reverse Waiting Time Distribution has been suggested as a likelihood based model to estimate the latent exposure status, and we therefore suggest to extend this into a joint likelihood based model, which incorporates both the latent exposure status and the exposure-outcome association. This will achieve consistency and efficiency of the estimates, i.e. they can be expected to be asymptotically unbiased and have optimal precision. METHODS: We established a joint likelihood for the observed case-control status and last prescription redemption before the index date. The likelihood combines the ordinary logistic regression likelihood and the reverse Waiting Time Distribution, and allows inclusion of covariates in both parts to adjust for observed confounders. We conducted a simulation study of the new model and standard models based on decision rules for exposure and the probability of being exposed, respectively, to assess the relative bias and variability of estimates. Lastly, we applied the models to a case-control study on use of nonsteroidal anti-inflammatory drugs and risk of upper-gastrointestinal bleeding. RESULTS: In simulation studies the new model had low relative bias (< 1.4%) and largely retained nominal coverage probabilities (90.2% to 95.1% of nominal 95% confidence intervals), also when moderate misspecification was introduced. All standard methods generally had substantial bias (-21.1% to 17.0%) and low coverage probabilities (0.0% to 68.9%). When analyzing the empirical case-control study, the new method estimated the effect of nonsteroidal anti-inflammatory drugs on risk of with upper-gastrointestinal bleeding hospitalization to 2.52 (1.59 - 3.45), whereas the other methods had estimates ranging from 3.52 (2.19 - 5.65) to 5.17 (2.40 - 11.11). CONCLUSIONS: Unlike standard methods, the proposed model gave nearly unbiased estimates with adequate coverage probabilities in simulation studies. The developed model demonstrates the potential for the reverse Waiting Time Distribution to be integrated with existing likelihood based analyses in pharmacoepidemiological studies.

Pharmacoepidemiological methods for computing the duration of pharmacological prescriptions using secondary data sources.

PURPOSE: In pharmacoepidemiology, correctly defining the exposure period of pharmacological treatment is a challenging step when information on the time in treatment is missing or incomplete. METHODS: In this review, we describe several methods for defining exposure to pharmacological treatments using secondary data sources that lack such information. RESULTS AND CONCLUSION: Several methods for assessing the duration of redeemed prescriptions and combining them into temporal sequences are available. We present a set of considerations to make researchers aware of the potentials and pitfalls of these methods that may aid in minimizing biases in research using these methods. Additionally, we highlight that, to date, there is no one-size-fits-all solution. Thus, the choice of method should be based on their area of applicability combined with a careful mapping to the research scenario under investigation.

Bottleneck analysis: Simple prediction of the precision of a planned case-control or cohort study based on healthcare registers.

PURPOSE: In pharmacoepidemiological studies, the precision of effect estimates usually depends on the lowest number in the underlying two by two table. We denote this the "bottleneck count" (BNC). We describe how to translate the BNC into an achievable precision and provide empirical examples. METHODS: First, we derive a theoretical prediction of the precision in a study where only the BNC determines precision. As an illustration, we calculated the expected precision of a null-effect study on retinoids and peptic ulcer bleeding, expressed as the upper/lower confidence limit ratio (ULCLR). Finally, we reviewed 126 effect estimates from the literature, analyzing the relationship between the predicted and achieved precision. RESULTS: The log-log transformed ULCLR was shown to be a simple linear function of log(BNC). The expected annual number of retinoid-users experiencing a peptic ulcer bleeding was 9.8, yielding an estimated ULCLR for a 1-year study of 3.84. The literature review showed an inverse linear relationship between the logarithmic BNC and the log-log transformed ULCLR, which was largely independent of study design, effect measure and category of BNC. Achieved precision deviated little from predictions but was usually lower than predicted, particularly with low BNC. CONCLUSION: The precision of a study can be predicted simply and with good accuracy from the BNC, which is useful for determining whether a study is worth pursuing or not.

Using multiple random index dates with the reverse waiting time distribution improves precision of estimated prescription durations.

PURPOSE: To improve the precision of prescription duration estimates when using the reverse waiting time distribution (rWTD). METHODS: For each patient we uniformly sampled multiple random index dates within a sampling window of length δ . For each index date, we identified the last preceding prescription redemption, if any, within distance δ . Based on all pairs of last prescription and index date, we estimated prescription durations using the rWTD with robust variance estimation. In simulation studies with increasing misspecification we investigated bias, root mean square error (RMSE) and coverage probability of the rWTD using multiple index dates (1, 5, 10, and 20). We applied the method to Danish data on warfarin prescriptions from 2013 to 2014 stratifying by and adjusting for sex and age. RESULTS: In simulation scenarios without misspecification, the relative bias was negligible (-0.04% to 0.01%) and nominal coverage probabilities almost retained (93.8%-95.4%). RMSE decreased with the number of random index dates (e.g., from 1.3 with 1 index date to 0.6 days with 5). With misspecification, the relative bias was higher irrespective of the number of index dates. Precision increased with the number of index dates, and hence coverage probabilities decreased. When estimating durations of warfarin prescriptions in Denmark, precision increased with number of index dates, in particular in strata with few patients (e.g., men 90+ years: width of 95% confidence interval was 16.2 days with 5 index dates versus 35.4 with 1). CONCLUSIONS: Increasing the number of random index dates used with the rWTD improved precision without affecting bias.

Predicting difference in mean survival time from cause-specific hazard ratios for women diagnosed with breast cancer.

BACKGROUND: Relative reduction in breast cancer mortality is the preferred outcome measure for evaluation of mammography screening. However, mean survival time has been advocated as a better and more intuitive outcome for risk communication. We have previously introduced a method to predict difference in mean survival time from empirical hazard ratios for all-cause mortality. In this article, we aim to investigate the association between hazard ratios for breast cancer mortality and the difference in mean survival time for women diagnosed with breast cancer. METHODS: We retrieved data on all women diagnosed with first-time invasive breast cancer in Norway from 1960 through 2004. Women were followed until emigration or end of follow-up on 31 December 2015, whichever came first. Observed differences in mean survival times and hazard ratios for both breast cancer death and death from causes other than breast cancer were obtained for neighbouring time periods defined by women's age and year of diagnosis. Based on previously developed methods, we fitted a linear relationship between observed differences in mean survival and logarithmic hazard ratios. RESULTS: A linear association was found between breast cancer-specific hazard ratios and difference in mean survival time for women diagnosed with breast cancer. This association was also estimated with adjustment for other causes of death than breast cancer. CONCLUSIONS: The change in mean survival time could be predicted from an estimated reduction in breast cancer mortality. This outcome measure can contribute to better and more understandable risk information about the effect of mammography screening programmes.

Adverse outcomes and mortality in users of non-steroidal anti-inflammatory drugs who tested positive for SARS-CoV-2: A Danish nationwide cohort study.

BACKGROUND: Concerns over the safety of non-steroidal anti-inflammatory drug (NSAID) use during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been raised. We studied whether use of NSAIDs was associated with adverse outcomes and mortality during SARS-CoV-2 infection. METHODS AND FINDINGS: We conducted a population-based cohort study using Danish administrative and health registries. We included individuals who tested positive for SARS-CoV-2 during the period 27 February 2020 to 29 April 2020. NSAID users (defined as individuals having filled a prescription for NSAIDs up to 30 days before the SARS-CoV-2 test) were matched to up to 4 non-users on calendar week of the test date and propensity scores based on age, sex, relevant comorbidities, and use of selected prescription drugs. The main outcome was 30-day mortality, and NSAID users were compared to non-users using risk ratios (RRs) and risk differences (RDs). Secondary outcomes included hospitalization, intensive care unit (ICU) admission, mechanical ventilation, and acute renal replacement therapy. A total of 9,236 SARS-CoV-2 PCR-positive individuals were eligible for inclusion. The median age in the study cohort was 50 years, and 58% were female. Of these, 248 (2.7%) had filled a prescription for NSAIDs, and 535 (5.8%) died within 30 days. In the matched analyses, treatment with NSAIDs was not associated with 30-day mortality (RR 1.02, 95% CI 0.57 to 1.82, p = 0.95; RD 0.1%, 95% CI -3.5% to 3.7%, p = 0.95), risk of hospitalization (RR 1.16, 95% CI 0.87 to 1.53, p = 0.31; RD 3.3%, 95% CI -3.4% to 10%, p = 0.33), ICU admission (RR 1.04, 95% CI 0.54 to 2.02, p = 0.90; RD 0.2%, 95% CI -3.0% to 3.4%, p = 0.90), mechanical ventilation (RR 1.14, 95% CI 0.56 to 2.30, p = 0.72; RD 0.5%, 95% CI -2.5% to 3.6%, p = 0.73), or renal replacement therapy (RR 0.86, 95% CI 0.24 to 3.09, p = 0.81; RD -0.2%, 95% CI -2.0% to 1.6%, p = 0.81). The main limitations of the study are possible exposure misclassification, as not all individuals who fill an NSAID prescription use the drug continuously, and possible residual confounding by indication, as NSAIDs may generally be prescribed to healthier individuals due to their side effects, but on the other hand may also be prescribed for early symptoms of severe COVID-19. CONCLUSIONS: Use of NSAIDs was not associated with 30-day mortality, hospitalization, ICU admission, mechanical ventilation, or renal replacement therapy in Danish individuals who tested positive for SARS-CoV-2. TRIAL REGISTRATION: The European Union electronic Register of Post-Authorisation Studies EUPAS34734.

Hypertensive disorders in pregnancy and timing of pubertal development in daughters and sons.

STUDY QUESTION: Do maternal hypertensive disorders affect pubertal development in daughters and sons? SUMMARY ANSWER: Pubertal development tended to occur earlier in daughters of mothers with 'preeclampsia, eclampsia or HELLP syndrome' (hemolysis, elevated liver enzymes and low blood platelets) or hypertension in pregnancy compared to daughters born of normotensive mothers. WHAT IS KNOWN ALREADY: The existing literature suggests some or no association between preeclampsia and pubertal development in daughters, but not in sons. None of the previous studies has investigated the possible association between other types of hypertensive disorders (hypertension, eclampsia or HELLP syndrome) and pubertal timing in children. STUDY DESIGN, SIZE, DURATION: Longitudinal cohort study consisting of 15 819 mother-child pairs with information on maternal hypertensive disorders collected during pregnancy and information on pubertal development collected half-yearly from the age of 11 years and until fully developed or 18 years of age. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants are children from the Puberty Cohort nested within the Danish National Birth Cohort. The exposure was register-based and self-reported information on maternal hypertensive disorders during pregnancy. The outcomes were children's self-reported information on pubertal development, including Tanner stage 1-5 (pubic hair (both daughters and sons) and breast development (daughters) or genital development (sons)), first menstrual bleeding (daughters) or first ejaculation (sons), voice break episode (sons), axillary hair development and acne occurrence (both daughters and sons). The main outcome was mean difference in age at attaining each pubertal milestone and a combined pubertal marker in children of mothers with hypertensive disorders in pregnancy (either hypertension (n = 490), 'preeclampsia, eclampsia or HELLP syndrome' (n = 419) or 'unspecific hypertensive disorders' (n = 334) with unexposed children as reference (n = 14 576)). MAIN RESULTS AND THE ROLE OF CHANCE: In daughters of mothers with 'preeclampsia, eclampsia or HELLP syndrome', we observed tendencies of earlier pubertal timing (combined marker: -2.0 (95% CI: -3.9; 0.0) months). In daughters of mothers with hypertension, several pubertal milestones tended to occur earlier than in daughters of normotensive mothers; however, all 95% CIs overlapped the null resulting in a combined pubertal marker of -1.0 (95% CI: -3.2; 1.1) months. In sons of mothers with any of the hypertensive disorders, we observed no difference in pubertal timing (combined markers: 'preeclampsia, eclampsia or HELLP syndrome': 0.1 (95% CI: -2.0; 2.1) months; hypertension: -0.6 (95% CI: -2.3; 1.1) months; 'unspecific hypertensive disorders': 0.2 (95% CI: -1.9; 2.2) months). LIMITATIONS, REASONS FOR CAUTION: The study is subject to non-differential misclassification of self-reported information on maternal hypertensive disorders in pregnancy and current pubertal status; possibly causing bias toward the null. WIDER IMPLICATIONS OF THE FINDINGS: Hypertensive disorders in pregnancy might accelerate pubertal timing in daughters; however, more studies are needed for causal conclusions. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the Faculty of Health at Aarhus University. The authors have no financial relationships or competing interests to disclose. TRIAL REGISTRATION NUMBER: N/A.

Using the waiting time distribution with random index dates to estimate prescription durations in the presence of seasonal stockpiling.

PURPOSE: A pervasive problem in registry-based pharmacoepidemiological studies is what exposure duration to assign to individual prescriptions. The parametric waiting time distribution (WTD) has been proposed as a method to estimate such durations. However, when prescription durations vary due to seasonal stockpiling, WTD estimates will vary with choice of index date. To counter this, we propose using random index dates. METHODS: Within a calendar period of a given length, δ, we randomly sample individual index dates. We include the last prescription redemption prior to the index date in the analysis. Only redemptions within distance δ of the index date are included. In a simulation study with varying types and degrees of stockpiling at the end of the year, we investigated bias and precision of the reverse WTD with fixed and random index dates, respectively. In addition, we applied the new method to estimate durations of Norwegian warfarin prescriptions in 2014. RESULTS: In simulation settings with stockpiling, the reverse WTD with random index dates had low relative biases (-0.65% to 6.64%) and high coverage probabilities (92.0% to 95.3%), although when stockpiling was pronounced, coverage probabilities decreased (2.7% to 85.8%). Using a fixed index date was inferior. The estimated duration of warfarin prescriptions in Norway using random index dates was 131 (130; 132) days. CONCLUSIONS: In the presence of seasonal stockpiling, the WTD with random index dates provides estimates of prescription durations, which are more stable, less biased and with better coverage when compared to using a fixed index date.

Effect of organized mammography screening on breast cancer mortality: A population-based cohort study in Norway.

We aimed to estimate the effect of organized mammography screening on incidence-based breast cancer mortality by comparing changes in mortality among women eligible for screening to concurrent changes in younger and older ineligible women. In a county-wise balanced, open-cohort study, we used birth cohorts (1896-1982) to construct three age groups in both the historical and screening period: women eligible for screening, and younger or older women ineligible for screening. We included women diagnosed with breast cancer who died within the same age-period group during 1987-2010 (n = 4,903). We estimated relative incidence-based mortality rate ratios (relative MRR) comparing temporal changes in eligible women to concurrent changes in ineligible women. Additionally, we conducted analyses comparing the change in eligible women to younger, ineligible women with either continued accrual and follow-up period (eligible women only) or continued follow-up period. All three age groups experienced a reduction in mortality, but the decrease among eligible women was about the same among ineligible women (relative MRR = 1.05, 95% CI: (0.94-1.18)). Varying the definition of follow-up yielded similar results. Mammography screening was not associated with a larger breast cancer mortality reduction in women eligible relative to ineligible women.

Timing of puberty in boys and girls: A population-based study.

BACKGROUND: A secular trend towards earlier puberty has been observed in girls, while a similar trend has been more uncertain in boys. We estimated current ages at pubertal development in both boys and girls. METHODS: In this population-based cohort study, 14 759 of 22 439 invited boys and girls born from 2000 to 2003 in the Danish National Birth Cohort gave half-yearly self-reported information on puberty from the age of 11.5 years and throughout puberty. This late start of follow-up limits the estimation of age at onset of puberty but not later pubertal milestones. We estimated mean age at attaining the following pubertal milestones in years with 95% confidence intervals (CI): age at menarche, voice break, first ejaculation of semen and Tanner stages for pubic hair development and breast development or genital development. Further, the difference in mean age at menarche between mothers and daughters was estimated. RESULTS: In boys, voice break occurred at 13.1 (95% CI 13.0, 13.1) years, first ejaculation of semen occurred at 13.4 (95% CI 13.3, 13.4) years, and Tanner Genital Stage 5 occurred at 15.6 (95% CI 15.5, 15.6) years. In girls, age at menarche occurred at 13.0 (95% CI 13.0, 13.1) years and Tanner Breast Stage 5 occurred at 15.8 (95% CI 15.7, 15.9) years. Daughters had menarche 3.6 (95% CI 3.1, 4.2) months earlier than their mothers had. CONCLUSION: These data indicate that age at menarche has declined and to some extent support a decline in age at attaining other markers of pubertal development among boys.

Empirical validation of the reverse parametric waiting time distribution and standard methods to estimate prescription durations for warfarin.

PURPOSE: In many prescription databases, the duration of treatment for the single prescription is not recorded. This study aimed to validate 2 different types of approaches for estimating prescription durations, using the oral anticoagulant warfarin as a case. METHODS: The approaches undergoing empirical validation covered assumptions of a fixed daily intake of either 0.5 or 1.0 defined daily dose (DDD), as well as estimates based on the reverse parametric waiting time distribution (rWTD), with different sets of covariates. We converted estimates of prescription duration to daily dose and compared them to prescribed daily dose as recorded in a clinical registry (using Bland-Altman plots). Methods were compared based on their average prediction error (logarithmic scale) and their limit of agreement ratio (ratio of mean error ± 1.96 SD after transformation to original scale). RESULTS: Estimates of daily doses were underestimated by 19% or overestimated by 62% when assumptions of 0.5 or 1.0 DDD were applied. The limit of agreement ratio was 6.721 for both assumptions. The rWTD-based approaches performed better when using the estimated mean value of the inter-arrival density, yielding on average negligible bias (relative difference of 0 to 2%) and with limit of agreement ratios decreasing upon additional covariate adjustment (from 6.857 with no adjustment to 4.036 with the fully adjusted model). CONCLUSIONS: Comparing the different methods, the rWTD algorithm performed best and led to unbiased estimates of prescribed doses and thus prescription durations and reduced misclassification on the individual level upon inclusion of covariates.