Estimands for atopic dermatitis clinical trials: Expert opinion on the importance of intercurrent events.

Despite the emergence of novel targeted treatments for atopic dermatitis (AD), there is a lack of guidelines on standardizing analysis of clinical trial data. To define and estimate meaningful treatment comparisons, several factors, including intercurrent events, must be taken into account. Intercurrent events are defined as events occurring after treatment initiation that affect either the interpretation or existence of the measurements associated with clinical questions of interest. Due to the relapsing, unpredictable nature of AD, intercurrent events frequently occur in AD trials, such as use of rescue therapy for intense itch and sleep deprivation. Despite the impact of intercurrent events in AD, they are often handled in an inconsistent manner across trials, which limits results interpretation. The estimand framework is increasingly used to estimate treatment effects while accounting for intercurrent events. This review explores how guidance from the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) on the use of estimands can be applied to support AD clinical trial design and analysis. We propose that estimands are used in AD trials and defined early during trial design. The use of estimands can provide clinicians with interventional trial results that are more reflective of clinical practice, help facilitate comparisons across clinical trials, and are more informative to enable improved treatment selection for patients.

'25-Hydroxyvitamin D, Autoantigenic and Total Antibody Concentrations: Results from a Danish Case-control Study of Newly Diagnosed Patients with Childhood Type 1 Diabetes and their Healthy Siblings'.

B cells have recently entered the stage as an important accessory player in type 1 diabetes (T1D) etiopathogenesis. Experimental studies suggest regulatory functions of vitamin D on B cells. However, only a few human studies, with considerable methodological limitations, have been conducted within this field. Our objective was to investigate whether higher 25-hydroxyvitamin D (25(OH)D) concentrations were inversely associated with ß-cell autoantigens glutamic acid decarboxylase (isoform 65) (GADA) and insulinoma-associated antigen-2A (IA-2A). Further, we also wanted to examine the relationship between 25(OH)D and total antibody concentrations. We randomly selected 500 patients with newly diagnosed T1D and 500 siblings for 25(OH)D, antibody and genetic analysis from the population-based Danish Registry of Childhood and Adolescent Diabetes. The relative change (RC) in the mean concentration of GADA, IA-2A and antibody isotypes by a 10 nmol/l increase in 25(OH)D concentration was modelled by a robust log-normal regression model. We found no association between 25(OH)D and GADA [adjusted RC per 10 nmol/l increase: 1.00; 95% confidence interval (CI): 0.98-1.02] and IA-2A [adjusted RC per 10 nmol/l increase: 0.92; CI: 0.76-1.12]. Further, 25(OH)D was not associated with the total concentration of antibody isotypes [immunoglobulin (Ig)A, IgE, IgG and IgM]. All null findings were unaltered after adjustment for genetic variation in the vitamin D pathway. Physiological concentrations of 25(OH)D are unlikely to have a clinically important effect on antibody concentrations in a paediatric population of newly diagnosed patients with T1D and their healthy siblings.

No association between vitamin D levels around time of birth and later risk of developing oligo- and polyarticular juvenile idiopathic arthritis: a Danish case-cohort study.

OBJECTIVES: Basic and epidemiological studies on rheumatic autoimmune diseases have suggested an association between vitamin D levels around time of birth and disease risk. The literature on vitamin D and juvenile idiopathic arthritis (JIA) is scarce. We hypothesized that low levels of 25-hydroxyvitamin D [25(OH)D] around time of birth would be associated with increased risk of oligo- or polyarticular JIA. METHOD: We conducted a case-cohort study of validated cases diagnosed with oligo- and polyarticular JIA (1993-2012) and controls matched on date of birth. Cases and controls were born in the period 1983-2010. Cases were diagnosed using international criteria. The concentration of 25(OH)D was assessed from neonatal dried blood spot (DBS) samples using high-sensitivity liquid chromatography tandem mass spectrometry (LC-MS/MS). Odds ratios (ORs) were calculated using conditional logistic regression and a two-way analysis of variance (ANOVA) was used to test for season and birth year 25(OH)D variations. A total of 300 matched pairs were included in the statistical analyses. RESULTS: No significant association was found between levels of 25(OH)D and JIA risk in the adjusted model [OR (per 25 nmol/L increase) 1.2, 95% confidence interval (CI) 0.9-1.6, p = 0.2]. 25(OH)D levels were found to fluctuate significantly with season (p < 0.0001) and year (p < 0.0001). The median level of 25(OH)D was 34.4 nmol/L in cases and 31.5 nmol/L in controls. CONCLUSIONS: Our study does not support the hypothesis that a window of vulnerability exists around time of birth with regard to 25(OH)D levels and later JIA risk. Further studies should explore whether 25(OH)D levels during early pregnancy or infancy may influence JIA risk.

Optimum bolus wizard settings in insulin pumps in children with Type 1 diabetes.

AIM: To evaluate current insulin pump settings in an optimally regulated paediatric population using bolus wizard. METHODS: We used a retrospective study design to analyse data from 124 children on insulin pump therapy who had optimum HbA1c levels [< 59 mmol/mol (< 7.5%)] and no history of severe hypoglycaemic events. Bolus wizard settings were used to calculate the insulin to carbohydrate factors and insulin sensitivity factors. Multiple regression analysis was used to analyse the variables associated with the calculation factors. RESULTS: Insulin to carbohydrate factor varied from 276 in the youngest group to 424 in the oldest group, and increased according to age. Insulin sensitivity factor was highest in the group aged 6 to < 12 years, with a value of 125. Age, amount of carbohydrates, number of boluses per day and insulin per kg were all significantly associated with both calculation factors. Furthermore, duration of insulin pump treatment was significantly associated with insulin sensitivity factor and percentage bolus/basal was significantly associated with insulin to carbohydrate factor. Gender, diabetes duration and BMI were not associated with any of the calculation factors. CONCLUSION: Optimum insulin pump settings at pump initiation depend on both insulin requirements and use of the pump. Settings need to be individualized because the standardized calculation factors are not constant for children. There is a need to develop specific age- and insulin dose-dependent calculation factors.

The prevalence of the electrocardiographic J wave in the Petit Basset Griffon Vendéen compared to 10 different dog breeds.

INTRODUCTION: To investigate the prevalence and amplitudes of the electrocardiographic J wave in the Petit Basset Griffon Vendéen compared to 10 other dog breeds. ANIMALS: Electrocardiograms from 206 healthy dogs representing 11 dog breeds were included in the study. Besides Petit Basset Griffon Vendéen (PBGV; n = 23) 10 other dog breeds were included. MATERIALS AND METHODS: An electrocardiogram ruler was used for measuring the amplitudes of the J waves. The definition of a J wave was a positive deflection at the J point of ≥0.1 mV in more than 1 lead of the bipolar standard limb leads (I, II, III) or the unipolar standard limb leads (aVL and aVF). RESULTS: The prevalence of J waves in the PBGV (n = 23) was 91% (n = 21, standard error (SE) = 5.9%), which was significantly higher compared to seven other dog breeds (p < 0.05). The overall prevalence of J waves in all 11 dog breeds (n = 206) was 43% (n = 89, robust SE = 7.8%). There was no significant difference in the prevalence between male and female dogs (p = 0.79). Neither did age (p = 0.22) nor heart rate (p = 0.25) significantly affect the prevalence of J wave. CONCLUSIONS: The PBGV had the highest prevalence of J waves and the highest amplitudes compared to 10 other dog breeds. However J waves were also seen in other breeds. Therefore, J waves may be considered a normal variant on the canine electrocardiogram and should not be interpreted as cardiac disease.

Treatment intensification without improved HbA1c levels in children and adolescents with Type 1 diabetes mellitus.

AIMS: To examine trends in diabetes treatment in Danish children and adolescents with Type 1 diabetes mellitus, comparing treatment intensity with metabolic outcomes in the population, and to describe the challenges of population-based registries in a clinical setting with rapidly changing treatment methods. METHODS: This observational study is based on the Danish national population registry of childhood diabetes, which includes 99% of children diagnosed with Type 1 diabetes before the age of 15 years. We included 4527 people diagnosed between 2000 and 2012. Self-monitored blood glucose measurements, insulin injections/boluses, treatment method and metabolic control quantifications were analysed and adjusted for the effects of gender and ethnicity, the combined effect of age, visit year and duration, and for the random effects of individual and hospital settings. RESULTS: Treatment was intensified via an increasing number of self-monitored blood glucose measurements and injections/boluses. More than six injections/boluses and an increased number of self-monitored blood glucose measurements were significantly associated with lower metabolic control. No reduction, however, in the overall mean HbA1c concentration was observed between 2005 [66 mmol/mol (8.2%)] and 2012 [65 mmol/mol (8.1%)]. Changed registration practices in 2009 introduced artificial jumps in data. CONCLUSIONS: Intensifying treatment alone does not lead to improved metabolic control in the overall population despite the appearance of lower HbA1c in individuals with a greater number of self-monitored blood glucose measurements and injections/boluses. The contradictory results reflect difficulties in using observational studies to predict results of intervention in the individual. Data collected from population-based registries need to be adjusted continuously to reflect changes in care.

Testing effect of a drug using multiple nested models for the dose-response.

During development of a drug, typically the choice of dose is based on a Phase II dose-finding trial, where selected doses are included with placebo. Two common statistical dose-finding methods to analyze such trials are separate comparisons of each dose to placebo (using a multiple comparison procedure) or a model-based strategy (where a dose-response model is fitted to all data). The first approach works best when patients are concentrated on few doses, but cannot conclude on doses not tested. Model-based methods allow for interpolation between doses, but the validity depends on the correctness of the assumed dose-response model. Bretz et al. (2005, Biometrics 61, 738-748) suggested a combined approach, which selects one or more suitable models from a set of candidate models using a multiple comparison procedure. The method initially requires a priori estimates of any non-linear parameters of the candidate models, such that there is still a degree of model misspecification possible and one can only evaluate one or a few special cases of a general model. We propose an alternative multiple testing procedure, which evaluates a candidate set of plausible dose-response models against each other to select one final model. The method does not require any a priori parameter estimates and controls the Type I error rate of selecting a too complex model.

Nationwide reduction in the frequency of severe hypoglycemia by half.

AIMS: To examine contemporary rates of severe hypoglycemia (SH) and identify the effect of predictors of SH in a pediatric type 1 diabetes population. METHODS: The national diabetes register provided data on children residing in Denmark from 2008 to 2013 in this register-based population study. Robust Poisson regression models were applied. RESULTS: The study population [n = 2,715 (50.9 % boys), mean (SD) age at onset; 8.1 (4.0) years, diabetes duration; 5.6 (4.9) years] comprised 7,390 person-years of data and 561 events of SH. The overall incidence of SH was 7.6 per 100 person-years. The incidence rate peaked with 16.0 per 100 person-years in 2008 reaching a nadir of 4.9 in 2011. Overall, insulin pump reduced the rate of SH with 27 % compared to any pen treatment (P = 0.003). When stratifying pen treatment, premixed insulin increased the rate of SH by 1.9-fold (P = 0.0015) and NPH increased the rate by 1.6-fold (P = 0.003) versus pump treatment, whereas long-acting insulin analogues were comparable with pump treatment (P = 0.1485). We found no association of SH with glycemic control (P > 0.05). CONCLUSIONS: A nationwide halving in rates of severe hypoglycemia was observed during the study period independent of the prevailing average HbA1c level. Changes in diabetes care and successful educational programs may have influenced the lower incidence rate of severe hypoglycemia.

Maternal obesity and offspring dietary patterns at 9 months of age.

BACKGROUND/OBJECTIVES: Differences in the quality of complementary feeding between infants of obese and nonobese mothers have not been examined sufficiently. The aim of this paper was to compare dietary patterns, foods, nutrients and energy intakes of 9-month-old Danish infants in a cohort comprising obese mothers (SKOT II, n=184; SKOT, Danish abbreviation of small children's diet and well-being) with a cohort consisting mainly of nonobese mothers (SKOT I, n=329). SUBJECTS/METHODS: Dietary intake was assessed by 7-day records, and dietary patterns were identified by principal component analysis. RESULTS: SKOT I was characterized by a lower maternal body mass index (BMI) and a higher social class than SKOT II in relation to parental education and occupation. Infants in SKOT II had lower scores on a Health-Conscious Food pattern reflected at the food group level, for example, with lower intake of the food groups Fruit and Vegetable but higher intake of WheatBreadNoWholegrain in SKOT II compared with SKOT I. Moreover, SKOT II had shorter durations of breastfeeding, earlier introductions of complementary feeding, higher energy intake from protein but lower energy intakes from monounsaturated fatty acids and polyunsaturated fatty acids at 9 months. SKOT II had higher weight-for-age and length-for-age z-scores, but no differences in BMI z-scores, as compared with SKOT I at 9 months. CONCLUSIONS: Infants of obese mothers from a lower social class seem to have a less healthy diet and higher weight and length z-scores at 9 months. Therefore, the promotion of healthy complementary feeding might be beneficial for the prevention of health implications, such as obesity, later in life for these infants.

Genotype-phenotype correlation between the cardiac myosin binding protein C mutation A31P and hypertrophic cardiomyopathy in a cohort of Maine Coon cats: a longitudinal study.

OBJECTIVES: A missense mutation (A31P) in the cardiac myosin binding protein C gene has been associated with hypertrophic cardiomyopathy (HCM) in Maine Coon cats. The aim of this study was to investigate the effect of A31P on development of HCM, myocardial diastolic dysfunction detected by color tissue Doppler imaging and occurrence of cardiac death during longitudinal follow-up in a cohort of Maine Coon cats. ANIMALS: The original cohort comprised 282 cats (158 of wild-type genotype, 99 heterozygous for A31P and 25 homozygous for A31P). METHODS: Prospective longitudinal study including echocardiography and registration of survival. RESULTS: The median age at the initial examination was 1.7 years (range, 0.8-9.2 years) and 6.4% (18/282) of the cats were diagnosed with HCM. One hundred sixty-five cats were eligible for echocardiographic re-examination, and during an average follow-up period of 2.7 years an additional 6.7% (11/165) of the cats developed HCM. Survival data could be obtained for 262 of the cats originally included, and among these 9.2% (24/262) died of causes that met the study criteria for cardiac death. In the homozygous group 80% (20/25) of cats included were diagnosed with HCM and 48% (12/25) suffered cardiac death during follow-up. These results corresponded to a significantly higher risk for cats homozygous for A31P to develop HCM (p<0.001) and die from cardiac-related causes compared with both other genotypes (p<0.001). CONCLUSIONS: Homozygosity for A31P was associated with a high penetrance of HCM and a substantial risk for cardiac death in the study population.

Prevalence of hypertrophic cardiomyopathy in a cohort of British Shorthair cats in Denmark.

BACKGROUND: Familial hypertrophic cardiomyopathy (HCM) has been described previously in British Shorthair cats (BSH), but until now, no reports have been published describing the prevalence of the disease within this breed. OBJECTIVES: The aim of this study was to assess the prevalence of HCM in a large cohort of BSH and to evaluate the effect of sex, weight, and increasing age as potential risk factors for this disease. ANIMALS: Three hundred and twenty-nine BSH presented for routine HCM screening during a 4-year period. METHODS: Prospective cross-sectional study in which all cats were screened for HCM by conventional echocardiography. RESULTS: A total of 329 cats were examined, 214 females and 115 males, with a median age of 2.3 years (range, 0.8-14.1). Twenty-eight cats (8.5%) were classified as HCM-positive, 14 (4.3%) as equivocal, 282 (85.7%) as HCM-negative, and 5 (2.1%) were diagnosed with other cardiac diseases. The median age for diagnosis of HCM was 2.7 years (range, 0.9-14.1). Male cats had a significantly higher occurrence of HCM (20.4%) compared with the females (2.1%) corresponding to an odds ratio of 7.89 (95 % CI, 2.54-28.08) for males versus females adjusted for age and weight (P < .001). CONCLUSION: The BSH in our cohort had a high prevalence of HCM, often of early onset and with a significant male sex predisposition. We strongly recommend echocardiographic screening in this breed, especially cats used for breeding.

Explained variation in a fully specified model for data-grouped survival data.

An additive hazards model may be used to quantify the effect of genetic and environmental predictors on flowering of sugar beet plants recorded as data-grouped time-to-event data. Estimated predictor effects have an intuitive interpretation rooted in the underlying time dynamics of the flowering process. However, agricultural experiments are often designed using several plots containing a large number of plants that are subsequently being monitored. In this article, we consider an additive hazards model with an additional plot structure induced by latent shared frailty variables. This approach enables us to derive a method to assess the quality of predictors in terms of how much plot variation they explain. We apply the method to a large data set exploring flowering of sugar beet and conclude that the genetic predictor biotype, which has a strong effect, also explains a substantial amount of the plot variation. The method is also applied to a data set from medical research concerning days to virus positivity of serum samples in AIDS patients.

Long-term exposure to indoor air pollution and wheezing symptoms in infants.

Long-term exposure to air pollution is suspected to cause recurrent wheeze in infants. The few previous studies have had ambiguous results. The objective of this study was to estimate the impact of measured long-term exposure to indoor air pollution on wheezing symptoms in infants. We monitored wheezing symptoms in diaries for a birth cohort of 411 infants. We measured long-term exposure to nitrogen oxides (NO(x)), NO(2), formaldehyde, PM(2.5) and black smoke in the infants' bedrooms and analyzed risk associations during the first 18 months of life by logistic regression with the dichotomous end-point 'any symptom-day' (yes/no) and by standard linear regression with the end-point 'number of symptom-days'. The results showed no systematic association between risk for wheezing symptoms and the levels of these air pollutants with various indoor and outdoor sources. In conclusion, we found no evidence of an association between long-term exposure to indoor air pollution and wheezing symptoms in infants, suggesting that indoor air pollution is not causally related to the underlying disease. Practical Implications Nitrogen oxides, formaldehyde and fine particles were measured in the air in infants' bedrooms. The results showed no evidence of an association between long-term exposure and wheezing symptoms in the COPSAC birth cohort.

Cancer incidence among 1st generation migrants compared to native Danes--a retrospective cohort study.

STUDY AIMS: To investigate the incidence of cancer among 1st generation migrants compared to native Danes, including time trends in the risk of cancer among migrants. METHODS: A retrospective cohort study design. Migrants were matched 1:4 on age and sex with a Danish born reference population. The cohort was linked to the Danish Cancer Register and cancer cases among migrants (n=537) and native Danes (n=2829) were identified. RESULTS: The overall cancer incidence did not differ significantly between migrants from East Europe and native Danes; whereas migrants from the Middle East and North Africa had a significantly lower incidence. All migrants had a significantly lower incidence of breast and colorectal cancer but male migrants from East Europe had a significantly higher incidence of lung cancer. CONCLUSIONS: The overall cancer incidence among migrants was lower compared to native Danes. The time trends of the study are interesting and a relevant topic for further research.

The probiotic potential against vibriosis of the indigenous microflora of rainbow trout.

The antibacterial properties of the indigenous microflora of rainbow trout (Oncorhynchus mykiss Walbaum) and the potential use of inhibitory bacteria as fish probiotics were investigated. A total of 1018 bacteria and yeasts were isolated on tryptone soy agar (TSA) from skin, gills and intestine. Forty-five of these inhibited growth of the fish pathogenic bacterium Vibrio anguillarum in a well diffusion assay. The antagonism was most prominent among Pseudomonas spp., as 28 (66%) of the antagonistic bacteria belonged to this genus, despite constituting only 15% of the total tested flora. As pseudomonads are typically siderophore producers, chrome azurol S (CAS) agar was used as a semi-selective medium for isolation of antagonistic bacteria. On this medium, 75% of the iron-chelating strains were inhibitory to V. anguillarum. Eight strains out of a subset of 11 antagonists caused a 3-6 log unit reduction in the density of V. anguillarum [measured by polymerase chain reaction (PCR) detection in a most probable number (MPN) regimen] in a broth co-culture assay. Survival of rainbow trout infected with vibriosis was improved 13-43% by six out of nine antagonistic strains tested in vivo. All disease-protecting strains were pseudomonads, isolated from CAS plates, whereas two Carnobacterium spp. that were antagonistic in in vitro well diffusion assays did not alter the accumulated mortality of rainbow trout. The addition of live bacterial cultures to fish-rearing water may thus improve survival of the fish; however, in vitro antagonism could not completely predict an in vivo effect. Further studies on the underlying mechanism of activity are required to design appropriate selection criteria for fish probiotic bacteria.