Network meta-analysis of (individual patient) time to event data alongside (aggregate) count data

Objectives: Network meta-analysis (NMA) methods extend the standard pair-wise framework to allow simultaneous comparison of multiple interventions in a single statistical model. Despite published work on NMA mainly focussing on the synthesis of aggregate data (AD), methods have been developed that allow the use of individual patient-level data (IPD) specifically when outcomes are dichotomous or continuous. This paper focuses on the synthesis of IPD and AD time to event data, motivated by a real data example looking at the effectiveness of high compression treatments on the healing of venous leg ulcers. Methods: This paper introduces a novel NMA modelling approach that allows IPD (time to event with censoring) and AD (event count for a given follow-up time) to be synthesised jointly by assuming an underlying, common, distribution of time to healing. Alternative model assumptions were tested within the motivating example. Model fit and adequacy measures were used to compare and select models. Results: Due to the availability of IPD in our example we were able to use a Weibull distribution to describe time to healing; otherwise, we would have been limited to specifying a uniparametric distribution. Absolute effectiveness estimates were more sensitive than relative effectiveness estimates to a range of alternative specifications for the model. Conclusions: The synthesis of time to event data considering IPD provides modelling flexibility, and can be particularly important when absolute effectiveness estimates, and not just relative effect estimates, are of interest

A Recurrent Germline Mutation in the 5'UTR of the Androgen Receptor Causes Complete Androgen Insensitivity by Activating Aberrant uORF Translation

A subset of patients with monogenic disorders lacks disease causing mutations in the protein coding region of the corresponding gene. Here we describe a recurrent germline mutation found in two unrelated patients with complete androgen insensitivity syndrome (CAIS) generating an upstream open reading frame (uORF) in the 5’ untranslated region (5’-UTR) of the androgen receptor (AR) gene. We show in patient derived primary genital skin fibroblasts as well as in cell-based reporter assays that this mutation severely impacts AR function by reducing AR protein levels without affecting AR mRNA levels. Importantly, the newly generated uORF translates into a polypeptide and the expression level of this polypeptide inversely correlates with protein translation from the primary ORF of the AR thereby providing a model for AR-5′UTR mediated translational repression. Our findings not only add a hitherto unrecognized genetic cause to complete androgen insensitivity but also underline the importance of 5′UTR mutations affecting uORFs for the pathogenesis of monogenic disorders in general

Identification of an AR mutation-negative class of androgen insensitivity by determining endogenous AR activity

Context: Only approximately 85%of patients with a clinical diagnosis complete androgen insensitivity syndrome and less than 30%with partial androgen insensitivity syndrome can be explained by inactivating mutations in the androgen receptor (AR) gene. Objective: The objective of the study was to clarify this discrepancy by in vitro determination of AR transcriptional activity in individuals with disorders of sex development (DSD) and male controls. Design: Quantification of DHT-dependent transcriptional induction of the AR target gene apolipoprotein D (APOD) in cultured genital fibroblasts (GFs) (APOD assay) and next-generation sequencing of the complete coding and noncoding AR locus. Setting: The study was conducted at a university hospital endocrine research laboratory. Patients: GFs from 169 individuals were studied encompassing control males (n=68), molecular defined DSD other than androgen insensitivity syndrome (AIS; n = 18), AR mutation-positive AIS (n = 37), and previously undiagnosed DSD including patients with a clinical suspicion of AIS (n=46). Intervention(s): There were no interventions. Main Outcome Measure(s): DHT-dependent APOD expression in cultured GF and AR mutation status in 169 individuals was measured. Results:TheAPODassay clearly separated control individuals (healthy malesandmolecular defined DSD patients other than AIS) from genetically proven AIS (cutoff<2.3-foldAPOD-induction;100%sensitivity, 93.3%specificity, P < .0001). Of 46 DSD individuals with no AR mutation, 17 (37%) fell below the cutoff, indicating disrupted androgen signaling. Conclusions:ARmutation-positive AIS canbereliably identified by theAPODassay. Its combination with next-generation sequencing of the AR locus uncovered an AR mutation-negative, new class of androgen resistance, which we propose to name AIS type II. Our data support the existence of cellular components outside the AR affecting androgen signaling during sexual differentiation with high clinical relevance