Editorial statistics

Development and application of statistical models for medical scientific researc

Editorial statistics

Development and application of statistical models for medical scientific researc

Choosing and changing the analysis scale in non-inferiority trials with a binary outcome

Algorithms and the Foundations of Software technolog

External validation of a dynamic prediction model for repeated predictions of natural conception over time

This work was supported by a Chief Scientist Office postdoctoral training fellowship in health services research and health of the public research (ref PDF/12/06). There are no conflicts of interest.Peer reviewedPostprin

Estimation of incident dynamic AUC in practice

The incident/dynamic time-dependent AUC (Area Under the ROC Curve) is an appealing measure to express the discriminative value of a dynamic survival model over time. However, estimation of this measure is not straightforward. Four recently proposed estimation approaches are studied. In an extensive simulation study, a head-to-head comparison between these four estimation methods is made. The estimation algorithms of some of the methods are extended. Results are illustrated with a motivating dynamic survival model from Reproductive Medicine. (C) 2020 The Authors. Published by Elsevier B.V.Development and application of statistical models for medical scientific researc

IVF for unexplained subfertility : whom should we treat?

Acknowledgements The authors would like to thank Tenovus Scotland and the Amsterdam Reproduction & Development Research Group for funding this project. We acknowledge the data management support of the Grampian Data Safe Haven (DaSH) and the associated financial support of NHS Research Scotland, through NHS Grampian investment in the Grampian DaSH. For more information, visit the DaSH website http://www.abdn.ac.uk/iahs/facilities/grampian-data-safe-haven.php. Funding Tenovus Scotland [grant G17.04], travel was supported by the Amsterdam Reproduction & Development Research Group [grant V.000296 to RvE].Peer reviewedPostprin

Tell me what you want, what you really really want: estimands in observational pharmacoepidemiologic comparative effectiveness and safety studies

Purpose: Ideally, the objectives of a pharmacoepidemiologic comparative effectiveness or safety study should dictate its design and data analysis. This paper discusses how defining an estimand is instrumental to this process.Methods: We applied the ICH-E9 (Statistical Principles for Clinical Trials) R1 addendum on estimands - which originally focused on randomized trials - to three examples of observational pharmacoepidemiologic comparative effectiveness and safety studies. Five key elements specify the estimand: the population, contrasted treatments, endpoint, intercurrent events, and population-level summary measure.Results: Different estimands were defined for case studies representing three types of pharmacological treatments: (1) single-dose treatments using a case study about the effect of influenza vaccination versus no vaccination on mortality risk in an adult population of =60 years of age; (2) sustained-treatments using a case study about the effect of dipeptidyl peptidase 4 inhibitor versus glucagon-like peptide-1 agonist on hypoglycemia risk in treatment of uncontrolled diabetes; and (3) as needed treatments using a case study on the effect of nitroglycerin spray as-needed versus no nitroglycerin on syncope risk in treatment of stabile angina pectoris.Conclusions: The case studies illustrated that a seemingly clear research question can still be open to multiple interpretations. Defining an estimand ensures that the study targets a treatment effect that aligns with the treatment decision the study aims to inform. Estimand definitions further help to inform choices regarding study design and data-analysis and clarify how to interpret study findings.Clinical epidemiolog

Birthweight of children with isolated congenital heart disease: a sibling analysis study

ObjectiveCongenital heart disease (CHD) is associated with decreased birthweight (BW) compared to population-based references. The aim of this study was to compare the BW of isolated CHD cases to their siblings, thus controlling for unknown and unmeasured confounders within the family. MethodsAll isolated CHD cases in the Leiden University Medical Center were included (2002-2019). Generalized estimated equation models were constructed to compare BW z scores of CHD neonates with their siblings. Cases were clustered to minor or severe CHD and stratified according to the aortic flow and oxygenation to the brain. ResultsThe overall BW z score of siblings was 0.032 (n = 471). The BW z score was significantly lower in CHD cases (n = 291) compared to their siblings (-0.20, p = 0.005). The results were consistent in the subgroup analysis of severe and minor CHD (BW z score difference -0.20 and -0.10), but did not differ significantly (p = 0.63). Stratified analysis regarding flow and oxygenation showed no BW difference between the groups (p = 0.1). ConclusionIsolated CHD cases display a significantly lower BW z score compared to their siblings. As the siblings of these CHD cases show a BW distribution similar to the general population, this suggests that shared environmental and maternal influences between siblings do not explain the difference in BW.Research into fetal development and medicin

Seasonal variation of serotonin turnover in human cerebrospinal fluid, depressive symptoms and the role of the 5-HTTLPR.

Studying monoaminergic seasonality is likely to improve our understanding of neurobiological mechanisms underlying season-associated physiological and pathophysiological behavior. Studies of monoaminergic seasonality and the influence of the serotonin-transporter-linked polymorphic region (5-HTTLPR) on serotonin seasonality have yielded conflicting results, possibly due to lack of power and absence of multi-year analyses. We aimed to assess the extent of seasonal monoamine turnover and examined the possible involvement of the 5-HTTLPR. To determine the influence of seasonality on monoamine turnover, 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were measured in the cerebrospinal fluid of 479 human subjects collected during a 3-year period. Cosine and non-parametric seasonal modeling were applied to both metabolites. We computed serotonin (5-HT) seasonality values and performed an association analysis with the s/l alleles of the 5-HTTLPR. Depressive symptomatology was assessed using the Beck Depression Inventory-II. Circannual variation in 5-HIAA fitted a spring-peak cosine model that was significantly associated with sampling month (P=0.0074). Season of sampling explained 5.4% (P=1.57 × 10(-7)) of the variance in 5-HIAA concentrations. The 5-HTTLPR s-allele was associated with increased 5-HIAA seasonality (standardized regression coefficient=0.12, P=0.020, N=393). 5-HIAA seasonality correlated with depressive symptoms (Spearman's rho=0.13, P=0.018, N=345). In conclusion, we highlight a dose-dependent association of the 5-HTTLPR with 5-HIAA seasonality and a positive correlation between 5-HIAA seasonality and depressive symptomatology. The presented data set the stage for follow-up in clinical populations with a role for seasonality, such as affective disorders