Treatment-independent live birth after in-vitro fertilisation : a retrospective cohort study of 2,133 women

Acknowledgements 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. We would like to thank all the staff at Aberdeen Fertility Clinic for their help with database queries and case note searching. Funding This work was funded by a Chief Scientist Office Postdoctoral Training Fellowship in Health Services Research and Health of the Public Research (Ref PDF/12/06). The views expressed here are those of the authors and not necessarily those of the Chief Scientist Office. The funder did not have any role in the study design, in the collection, analysis, and interpretation of data, in the writing of the report nor in the decision to submit the paper for publication.Peer reviewedPostprin

A comparison of the beta-geometric model with landmarking for dynamic prediction of time to pregnancy

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Prioritizing IVF treatment in the post-COVID 19 era : a predictive modelling study based on UK national data

Acknowledgements We thank the Human Fertilization and Embryological Authority for permission to analyse their database, extracting the requested information and assisting with our queries in an efficient manner. We also 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 (www.abdn.ac.uk/iahs/facilities/grampian-data-safe-haven.php). Funding: No external funding was received for this study. We plan to disseminate the results to patient organisations and the Human Fertilisation and Embryology AuthorityPeer 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

Continuous glucose monitoring metrics and pregnancy outcomes in insulin-treated diabetes : A post-hoc analysis of the GlucoMOMS trial

Funding Information: BWM is supported by a NHMRC investigatorgrant (GNT1176437) and BWM reports consultancy, travel support and research funding from Merck. All other authors declare no conflict of interest. The GlucoMOMS trial was funded by ZonMw, the Dutch Organisation for Health Research and Development, project number 80‐82310‐97‐11157. Continuous Glucose Monitors were purchased at a discount price at Medtronic®, Heerlen, The Netherlands. Neither ZonMw nor Medtronic had a role in study design, data collection, data analysis, data interpretation, or writing of the reports of either the original study or the current post hoc analysis. 10 Publisher Copyright: © 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.Peer reviewedPublisher PD

Epigenetic mapping of the metabolome reveals mediators of the epigenotype-phenotype map

Identifying the sources of natural variation underlying metabolic differences between plants will enable a better understanding of plant metabolism and provide insights into the regulatory networks that govern plant growth and morphology. So far, however, the contribution of epigenetic variation to metabolic diversity has been largely ignored. In the present study, we utilized a panel of Arabidopsis thaliana epigenetic recombinant inbred lines (epiRILs) to assess the impact of epigenetic variation on the metabolic composition. Thirty epigenetic QTL (QTLepi) were detected, which partly overlap with QTLepi linked to growth and morphology. In an effort to identify causal candidate genes in the QTLepi regions and their putative trans-targets, we performed in silico small RNA and qPCR analyses. Differentially expressed genes were further studied by phenotypic and metabolic analyses of knockout mutants. Three genes were detected that recapitulated the detected QTLepi effects, providing evidence for epigenetic regulation in cis and in trans These results indicate that epigenetic mechanisms impact metabolic diversity, possibly via small RNAs, and thus aid in further disentangling the complex epigenotype-phenotype map

Hyperemesis gravidarum severity, enteral tube feeding and cardiometabolic markers in offspring cord blood

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Prognosis-based management of couples with unexplained subfertility

One out of nine heterosexual couples who are trying to conceive, do not succeed within one year of trying. This is referred to as subfertility. In almost half of subfertile couples, no explanation for their inability to conceive can be found during check-ups. This ‘unexplained’ subgroup represents a clinical dilemma: there is no clinical indication that treatment, for instance using in vitro fertilisation, will solve the physical problem, especially given that these couples can still conceive naturally. The pregnancy chance when trying to conceive naturally for a longer period of time i.e. the prognosis is key in deciding (when) to treat. Not all couples benefit from starting treatment immediately. Due to selection, in which couples with a good prognosis conceive and those with a poorer prognosis do not, the average chance of natural conception decreases as couples try to conceive for a longer period of time. This thesis provides individualised prognoses i.e. pregnancy chances after trying to conceive naturally or when starting intrauterine insemination or in vitro fertilisation at various points in time. Predictions were estimated using methods for dynamic prediction. In the absence of a clear diagnosis and a consensus on the best treatment trajectory, couples require prognostic information to make an informed, shared decision with their clinician on fertility treatment. The prognoses in this thesis can facilitate this decision making process and give couples with unexplained subfertility a realistic estimate of what they can expect from their treatment trajectory

Simultaneous sequential monitoring of efficacy and safety led to masking of effects

OBJECTIVE: Usually, sequential designs for clinical trials are applied on the primary (=efficacy) outcome. In practice, other outcomes (e.g., safety) will also be monitored and influence the decision whether to stop a trial early. Implications of simultaneous monitoring on trial decision making are yet unclear. This study examines what happens to the type I error, power, and required sample sizes when one efficacy outcome and one correlated safety outcome are monitored simultaneously using sequential designs. STUDY DESIGN AND SETTING: We conducted a simulation study in the framework of a two-arm parallel clinical trial. Interim analyses on two outcomes were performed independently and simultaneously on the same data sets using four sequential monitoring designs, including O'Brien-Fleming and Triangular Test boundaries. Simulations differed in values for correlations and true effect sizes. RESULTS: When an effect was present in both outcomes, competition was introduced, which decreased power (e.g., from 80% to 60%). Futility boundaries for the efficacy outcome reduced overall type I errors as well as power for the safety outcome. CONCLUSION: Monitoring two correlated outcomes, given that both are essential for early trial termination, leads to masking of true effects. Careful consideration of scenarios must be taken into account when designing sequential trials. Simulation results can help guide trial design