An enhanced version of FREM (Fracture Risk Evaluation Model) using national administrative health data: analysis protocol for development and validation of a multivariable prediction model.

BACKGROUND: Osteoporosis poses a growing healthcare challenge owing to its rising prevalence and a significant treatment gap, as patients are widely underdiagnosed and consequently undertreated, leaving them at high risk of osteoporotic fracture. Several tools aim to improve case-finding in osteoporosis. One such tool is the Fracture Risk Evaluation Model (FREM), which in contrast to other tools focuses on imminent fracture risk and holds potential for automation as it relies solely on data that is routinely collected via the Danish healthcare registers. The present article is an analysis protocol for a prediction model that is to be used as a modified version of FREM, with the intention of improving the identification of subjects at high imminent risk of fracture by including pharmacological exposures and using more advanced statistical methods compared to the original FREM. Its main purposes are to document and motivate various aspects and choices of data management and statistical analyses. METHODS: The model will be developed by employing logistic regression with grouped LASSO regularization as the primary statistical approach and gradient-boosted classification trees as a secondary statistical modality. Hyperparameter choices as well as computational considerations on these two approaches are investigated by an unsupervised data review (i.e., blinded to the outcome), which also investigates and handles multicollinarity among the included exposures. Further, we present an unsupervised review of the data and testing of analysis code with respect to speed and robustness on a remote analysis environment. The data review and code tests are used to adjust the analysis plans in a blinded manner, so as not to increase the risk of overfitting in the proposed methods. DISCUSSION: This protocol specifies the planned tool development to ensure transparency in the modeling approach, hence improving the validity of the enhanced tool to be developed. Through an unsupervised data review, it is further documented that the planned statistical approaches are feasible and compatible with the data employed.

Gender affirming hormonal treatment in Danish transgender persons: A nationwide register-based study.

BACKGROUND: Gender affirming hormonal treatment (GAHT) is a cornerstone in transgender care. National data are sparse regarding use of hormonal treatment by transgender persons. AIM: To assess use of GAHT in transgender persons. DESIGN: National register-based cohort study in Danish transgender persons followed from 2000 until 2018. The main outcome measure was prescription and purchase of GAHT. Persons with ICD-10 diagnosis code of "gender identity disorder" (CGI-cohort) and persons with legal sex change but without diagnosis (CPR-cohort) were included. In the CGI-cohort, transgender women were defined by prescription of estrogen and/or cyproterone acetate and/or testosterone-5-alpha reductase inhibitors, and transgender men were defined by prescription of testosterone after study inclusion. Discontinuation of GAHT was defined as no purchase of GAHT ≥13 months or shift from feminizing to masculinizing hormone treatment, or vice versa. RESULTS: The cohort included 2789 transgender persons (n = 1717, CGI-cohort and n = 1072, CPR-cohort). The median age (interquartile range) at study inclusion was 26.1 (17.7) years for persons assigned male at birth (n = 1447) and 22.5 (10.5) years for persons assigned female at birth (n = 1342). In the CGI-cohort, the event rate for GAHT in transgender women increased from 4.0 (95% confidence interval [CI]: [3.1; 5.2]) events per 100 person in year 2000-2005 to 20.6 (17.8; 23.7) between 2014 and 2018. In transgender men, the event rate of GAHT increased from 4.2 (2.8; 6.2) to 18.8 (16.4; 21.6). The rate of discontinuation of GAHT was 0.06 (95% CI 0.049; 0.071) per person year. CONCLUSIONS: The event rate of GAHT increased during 2000-2018. Our data suggested high adherence to GAHT.

Prediction of Long-term Survival After Status Epilepticus Using the ACD Score.

Importance: Early prediction of long-term mortality in status epilepticus is important given the high fatality rate in the years after diagnosis. Objective: To improve prognostication of long-term mortality after status epilepticus diagnosis. Design, Settings, and Participants: This retrospective, multicenter, multinational cohort study analyzed adult patients who were diagnosed with and treated for status epilepticus at university hospitals in Odense, Denmark, between January 1, 2008, and December 31, 2017, as well as in Oslo, Norway; Marburg, Germany; and Frankfurt, Germany. They were aged 18 years or older and had first-time, nonanoxic status epilepticus. A new scoring system, called the ACD score, for predicting 2-year (long-term) mortality after hospital discharge for status epilepticus was developed in the Danish cohort and validated in the German and Norwegian cohorts. The ACD score represents age at onset, level of consciousness at admission, and duration of status epilepticus. Data analysis was performed between September 1, 2019, and March 31, 2020. Exposures: Long-term follow-up using data from national and local civil registries in Denmark, Norway, and Germany. Main Outcomes and Measures: The predefined end point was 2-year survival for all patients and for a subgroup of patients with status epilepticus causes that were not damaging or were less damaging to the brain. Neurological deficits before and after onset, demographic characteristics, etiological categories of status epilepticus, comorbidities, survival, time points, treatments, and prognostic scores for different measures were assessed. Results: A total of 261 patients (mean [SD] age, 67.2 [14.8] years; 132 women [50.6%]) were included, of whom 145 patients (mean [SD] age, 66.3 [15.0] years; 78 women [53.8%]) had status epilepticus causes that were not damaging or were less damaging to the brain. The validation cohort comprised patients from Norway (n = 139) and Germany (n = 906). At hospital discharge, 29.8% of patients (n = 64 of 215) had new moderate to severe neurological deficits compared with baseline. New neurological deficits were a major predictor of 2-year survival after hospital discharge (odds ratio, 5.1; 95% CI, 2.2-11.8); this association was independent of etiological category. Nonconvulsive status epilepticus in coma and duration of status epilepticus were associated with development of new neurological deficits, and a simple 3-factor score (ACD score) combining these 2 risk factors with age at onset was developed to estimate survival after status epilepticus diagnosis. The ACD score had a linear correlation with 2-year survival (Pearson r2 = 0.848), especially in the subset of patients with a low likelihood of brain damage. Conclusions and Relevance: This study found that age, long duration, and nonconvulsive type of status epilepticus in coma were associated with the development of new neurological deficits, which were predictors of long-term mortality. Accounting for risk factors for new neurological deficits using the ACD score is a reliable method of prediction of long-term outcome in patients with status epilepticus causes that were not damaging or were less damaging to the brain.

Socioeconomic status in Danish transgender persons: a nationwide register-based cohort study.

BACKGROUND: Gender dysphoria could be associated with low socioeconomic status (SES). SES could be modified by age, ethnic background, and medical morbidity. AIM: To determine SES in a national study population including transgender persons in Denmark. METHODS: National register-based cohort study in Danish transgender persons and age-matched controls. The transgender study cohort included persons with ICD-10 diagnosis code of 'gender identity disorder' and/or persons with legal sex change and persons who fulfiled the inclusion criteria during 2000-2018. The main outcome measure was SES including personal income, occupational status, and education. RESULTS: The cohort included 2770 transgender persons and 27,700 controls. In the transgender study cohort, 1437 were assigned male at birth (AMAB), median age (interquartile range, IQR) 26.0 (17.3) years, and 1333 were assigned female at birth (AFAB), median age 22.5 (10.3) years. Adjusting for age and sex, the relative risk ratio (RRR) of low vs high personal income was 5.6 (95% CI: 4.9; 6.3) in transgender persons compared to controls. The RRR of low vs high income was 6.9 (5.8; 8.3) in persons AMAB compared to control males and 4.7 (3.9; 5.6) in persons AFAB compared to control females. The RRR of low vs high income was 3.7 (3.2; 4.3) in transgender persons of Danish origin compared to controls. The Charlson comorbidity index was comparable in transgender persons vs controls. CONCLUSIONS: Being transgender was negatively associated with SES. In transgender persons, the risk of low vs high income could be more pronounced in transgender persons of foreign origin.

A bivariate logistic regression model based on latent variables.

Bivariate observations of binary and ordinal data arise frequently and require a bivariate modeling approach in cases where one is interested in aspects of the marginal distributions as separate outcomes along with the association between the two. We consider methods for constructing such bivariate models based on latent variables with logistic marginals and propose a model based on the Ali-Mikhail-Haq bivariate logistic distribution. We motivate the model as an extension of that based on the Gumbel type 2 distribution as considered by other authors and as a bivariate extension of the logistic distribution, which preserves certain natural characteristics. Basic properties of the obtained model are studied and the proposed methods are illustrated through analysis of two data sets: a basic science cognitive experiment of visual recognition and awareness and a clinical data set describing assessments of walking disability among multiple sclerosis patients.

Typical Versus Atypical Antipsychotics for Acute Mania.

BACKGROUND: Mania is challenging to treat. Typical antipsychotics may be more efficient compared with atypical antipsychotics, however, with unfavorable side effects. STUDY QUESTION: To investigate the courses of acute manic episodes and correlations between changes of severity during manic episodes and type of antipsychotic treatment. STUDY DESIGN: This case record study included patients admitted with mania (International Classification of Diseases 10th revision code F30, F31.0, F31.1, F31.2 or F31.6) at the Department of Affective Disorders, Aarhus University Hospital from June 1, 2013 to April 1, 2016. MEASURES AND OUTCOMES: The doses of typical and atypical antipsychotics were standardized as defined daily dose according to the World Health Organization's guidelines. The severity of mania was measured up to 3 times daily with the Modified Bech-Rafaelsen Mania Scale (MAS-M), a nurse administered scale. We applied a linear regression in a mixed model approach to compare MAS-M score over time under the influence of typical plus atypical antipsychotics and atypical antipsychotics only. We further analyzed by mania with and without psychosis and by concomitant use of lithium and/or antiseizure medication. RESULTS: We included 56 admissions on 46 patients. The courses of the manic episodes measured by MAS-M varied between patients-both daily variations and changes over time. Patients receiving typical antipsychotics had higher baseline MAS-M, more recent admissions, and were mechanically constrained more often compared with patients receiving atypical antipsychotics only. Adjusted for age, gender, mechanical constraint, and dosage of antipsychotics, the difference in reduction of mania was -0.02 MAS-M points/d (95% confidence interval, -0.05 to 0.01) higher in the group receiving atypical antipsychotics only; however, it is not statistically or clinically significant. CONCLUSIONS: The rate of improvement of mania was similar in the two groups which supports that atypical antipsychotics can be recommended over typical antipsychotics to reduce risk of severe side effects.

Milk Products in the Treatment of Hypophosphatemic Rickets: A Pilot Study.

BACKGROUND: Standard treatment of hypophosphatemic rickets (HR) is oral phosphate tablets plus vitamin D. Due to the rapid absorption of phosphate tablets, frequent daily doses are necessary, which is cumbersome and may cause fluctuations in plasma phosphate and risk of secondary hyperparathyroidism. It was hypothesized that phosphate from milk or cheese is less rapidly absorbed, and reduces fluctuations in plasma phosphate. OBJECTIVES: The current randomized, multiple crossover study aimed at investigating if an equivalent phosphate dose given as milk or cheese is comparable to phosphate tablets in patients with HR. METHODS: Seven females with HR were included. They went through three different four-day treatment sessions of either oral phosphate tablets consisting of 800 mg elemental phosphorus divided into five doses over the day or an equivalent phosphorus dose ingested as skimmed milk or cheese divided over five daily doses. Blood and urine samples were taken from patients after each treatment session. Except the usual doses of vitamin D, no phosphate or calcium-modifying treatments were allowed. Statistical analyses were performed using mixed models. RESULTS: Treatment feasibility was independent of the phosphorus source. The study demonstrated reduced plasma levels of parathyroid hormone (PTH), reduced fluctuations in plasma phosphate and plasma PTH, and reduced renal phosphate excretion when ingesting phosphorus supplementation as milk compared to phosphate tablets. The same trend was observed when administering phosphorus as cheese, though not statistically significant. CONCLUSIONS: Phosphorus supplements can be administered as phosphate tablets, milk or cheese when given in equimolar doses. The current study findings indicated that milk may be superior to phosphate tablets as the phosphate source in patients with HR.

Perceived stress, disturbed sleep, and cognitive impairments in patients with work-related stress complaints: a longitudinal study.

Patients on sick leave due to work-related stress often present with cognitive impairments as well as sleep disturbances. The aim of this longitudinal study was to examine the role of perceived stress and sleep disturbances in the longitudinal development in cognitive impairments in a group of patients with prolonged work-related stress (N = 60) during a period of 12 months following initial professional care-seeking. Objective cognitive impairments (neuropsychological tests) were measured on two occasions - at initial professional care-seeking and at 12-month follow-up. Questionnaires on perceived stress, sleep disturbances, and cognitive complaints were completed seven times during the 12 months which facilitated multilevel analysis with segregation of within-person (change) and between-person (baseline level) components of the time-varying predictors (perceived stress and sleep disturbances). Change in perceived stress was associated with concurrent and subsequent change in self-reported cognitive complaints over the period of 12 months and to a lesser extent the change in performance on neuropsychological tests of processing speed from baseline to 12-month follow-up. Change in sleep disturbances was also associated with concurrent and subsequent change in self-reported cognitive complaints over the 12 months but not with change on neuropsychological test performance. Although the mechanism behind the improvement in cognitive impairments in patients with work-related stress should be further explored in future studies, the results could suggest that improvement in cognitive impairments is partly mediated by decreasing levels of perceived stress and, to a lesser extent, decreasing levels of sleep disturbances. Lay summary This study examines the role of perceived stress and sleep disturbances in respect to the development of cognitive impairments (e.g. memory and concentration) in a group of patients with work-related stress. We found that change in cognitive impairments seems to be partly explained by change in perceived stress and, to a lesser extent, sleep disturbances over time. This could suggest that cognitive impairments can be reduced by stress management interventions which aim to reduce perceived stress and sleep disturbances but future studies are needed to confirm this interpretation.