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It has been well established that randomized clinical trials have poor external validity, resulting in findings that may not apply to relevant—or target—populations. When the trial is sampled from the target population, generalizability methods have been proposed to address the applicability of trial findings to target populations. When the trial sample and target populations are distinct, transportability methods may be applied for this purpose. However, generalizability and transportability studies present challenges, particularly around the strength of their conclusions. We review and summarize state-of-the-art methods for translating trial findings to target populations. We additionally provide a novel step-by-step guide to address these challenges, illustrating principles through a published case study. When conducted with rigor, generalizability and transportability studies can play an integral role in regulatory decisions by providing key real-world evidence. [ABSTRACT FROM AUTHOR]

Inverse odds of participation weighting (IOPW) has been proposed to transport clinical trial findings to target populations of interest when the distribution of treatment effect modifiers differs between trial and target populations. We set out to apply IOPW to transport results from an observational study to a target population of interest. We demonstrated the feasibility of this idea with a real-world example using a nationwide electronic health record derived de-identified database from Flatiron Health. First, we conducted an observational study that carefully adjusted for confounding to estimate the treatment effect of fulvestrant plus palbociclib relative to letrozole plus palbociclib as a second-line therapy among estrogen receptor (ER)-positive, human epidermal growth factor receptor (HER2)-negative metastatic breast cancer patients. Second, we transported these findings to the broader cohort of patients who were eligible for a first-line therapy. The interpretation of the findings and validity of such studies, however, rely on the extent that causal inference assumptions are met. [ABSTRACT FROM AUTHOR]

To address potential safety concerns of Janus Kinase Inhibitors (JAK-Is), we characterized their safety profile in the atopic dermatitis (AD) patient population. In this retrospective observational study, we used propensity score-based methods and a Poisson modeling framework to estimate the incidence of health outcomes of interest (HOI) for the AD patient. To that end, two mutually exclusive cohorts were created using a real world data resource: a rheumatoid arthritis (RA) cohort, where we directly quantify the safety risk of JAK-Is on HOIs, and an AD cohort, that comprises the target population of interest and to whom we transport the results obtained from the RA cohort. The RA cohort included all adults who filled at least one prescription for a JAK-I (tofacitinib, baricitinib, or upadacitinib) between 1 January 2017 and 31 January 2020. The AD cohort consisted of all adults diagnosed with AD during the same period. We first estimated the incidence rate of each HOI in the RA cohort, and then transported the results to the AD population. The RA and AD cohorts included 5,296 and 261,855 patients, respectively. On average, patients in the AD cohort were younger, more often male, more likely to be Asian, and had higher household income. They also had a lower prevalence of several comorbid conditions including hypertension, chronic kidney disease, obesity, and depression. Overall, the transported incidence rates of the HOIs to the AD cohort were lower than those obtained in the RA cohort by 13–50%. We applied transportability methods to characterize the risk of the HOIs in the AD population and found absolute risks higher than that of the general population. Future work is needed to validate these conclusions in comparable populations. [ABSTRACT FROM AUTHOR]

Myelination in the central nervous system is the process by which oligodendrocytes form myelin sheaths around the axons of neurons. Myelination enables neurons to transmit information more quickly and more efficiently and allows for more complex brain functions; yet, remarkably, the underlying mechanism by which myelination occurs is still not fully understood. A reliable in vitro assay is essential to dissect oligodendrocyte and myelin biology. Hence, we developed a protocol to generate myelinating oligodendrocytes from mouse embryonic stem cells and established a myelin formation assay with embryonic stem cell-derived neurons in microfluidic devices. Myelin formation was quantified using a custom semi-automated method that is suitable for larger scale analysis. Finally, early myelination was followed in real time over several days and the results have led us to propose a new model for myelin formation. [ABSTRACT FROM AUTHOR]

The article presents an abstract of the study "The Role of Ephs and Ephrins in the Development of Oligodendrocytes," by Rick I. Cohen and colleagues, which will be presented at the 30th annual meeting of the American Society for Neurochemistry to be held from March 14-17, 1999 in New Orleans, Louisiana. The researchers analyzed the expression pattern of several genes from oligodendrocyte precursors using Microarray analysis in order to understand molecular mechanisms stimulated by IGF- 1.

Models for predicting the time of a future event are crucial for risk assessment, across a diverse range of applications. Existing time-to-event (survival) models have focused primarily on preserving pairwise ordering of estimated event times (i.e., relative risk). We propose neural time-to-event models that account for calibration and uncertainty while predicting accurate absolute event times. Specifically, an adversarial nonparametric model is introduced for estimating matched time-to-event distributions for probabilistically concentrated and accurate predictions. We also consider replacing the discriminator of the adversarial nonparametric model with a survival-function matching estimator that accounts for model calibration. The proposed estimator can be used as a means of estimating and comparing conditional survival distributions while accounting for the predictive uncertainty of probabilistic models. Extensive experiments show that the distribution matching methods outperform existing approaches in terms of both calibration and concentration of time-to-event distributions.

Objective: Glial progenitor cells are abundant in adult human white matter. This study was designed to identify signaling pathways regulating their self-renewal and fate., Methods: We compared the transcriptional profiles of freshly sorted adult human white matter progenitor cells (WMPCs), purified by A2B5-based immunomagnetic sorting, with those of the white matter from which they derived., Results: We identified 132 genes differentially expressed by WMPCs; these included principal components of five receptor-defined signaling pathways, represented by platelet derived growth factor receptor alpha (PDGFRA) and type 3 fibroblast growth factor receptor (FGFR3), receptor tyrosine phosphatase-beta/zeta (RTPZ), notch, and syndecan3. WMPCs also differentially expressed the bone morphogenetic protein 4 (BMP4) inhibitors neuralin and BAMBI (BMP and activin membrane-bound inhibitor), suggesting tonic defense against BMP signaling. Differential overexpression of RTPZ was accompanied by that of its modulators pleiotrophin, NrCAM, tenascin, and the chondroitin sulfate proteoglycans, suggesting the importance of RTPZ signaling to WMPCs. When exposed to the RTPZ inhibitor bpV(phen), or lentiviral-shRNAi against RTPZ, WMPCs differentiated as oligodendrocytes. Conversely, when neuralin and BAMBI were antagonized by BMP4, astrocytic differentiation was induced, which was reversible by noggin., Interpretation: The RTPZ and BMP pathways regulate the self-maintenance of adult human WMPCs, and can be modulated to induce their oligodendrocytic or astrocytic differentiation. As such, they provide targets by which to productively mobilize resident progenitor cells of the adult human brain.