Robust and Flexible Estimation of Stochastic Mediation Effects: A Proposed Method and Example in a Randomized Trial Setting

Causal mediation analysis can improve understanding of the mechanisms underlying epidemiologic associations. However, the utility of natural direct and indirect effect estimation has been limited by the assumption of no confounder of the mediator-outcome relationship that is affected by prior exposure---an assumption frequently violated in practice. We build on recent work that identified alternative estimands that do not require this assumption and propose a flexible and double robust semiparametric targeted minimum loss-based estimator for data-dependent stochastic direct and indirect effects. The proposed method treats the intermediate confounder affected by prior exposure as a time-varying confounder and intervenes stochastically on the mediator using a distribution which conditions on baseline covariates and marginalizes over the intermediate confounder. In addition, we assume the stochastic intervention is given, conditional on observed data, which results in a simpler estimator and weaker identification assumptions. We demonstrate the estimator's finite sample and robustness properties in a simple simulation study. We apply the method to an example from the Moving to Opportunity experiment. In this application, randomization to receive a housing voucher is the treatment/instrument that influenced moving to a low-poverty neighborhood, which is the intermediate confounder. We estimate the data-dependent stochastic direct effect of randomization to the voucher group on adolescent marijuana use not mediated by change in school district and the stochastic indirect effect mediated by change in school district. We find no evidence of mediation. Our estimator is easy to implement in standard statistical software, and we provide annotated R code to further lower implementation barriers.Comment: 24 pages, 2 tables, 2 figure

Process development approaches for expansion of adherent stem cells in microcarrier-based bioreactor culture

Industry trends in regenerative medicine show an increased need for scalable and closed manufacturing of cell therapies. Single-use bioreactor systems have proven suitable as a platform to meet the industry’s needs. Key process parameters for cell culture performance in these systems include pH, dissolved oxygen (DO) and agitation rates. Especially important is the understanding and application of appropriate solid-liquid mixing, which is essential for microcarrier-based cultures used for adherent stem cells. Agitation rates that are too high in microcarrier-based cultures can be correlated with smaller eddy lengths that impact cellular shear. Conversely, agitation rates that are low do not support the consistent microcarrier turnover required for cell access to nutrients, DO, and maintenance of pH. Moreover, suboptimal agitation rates may impact cell-to-microcarrier attachment and transfer. Here, we summarize a stepwise approach to optimizing pH, DO and agitation set-points in the Mobius® 3L single-use bioreactor for mesenchymal stem/stromal cells (MSCs). The theoretical agitation operating range best suited for microcarrier cultures was calculated based on the Zwietering equation for suspension of solids in stirred tanks, and verified experimentally with human bone marrow-derived MSCs. Upper agitation limits were defined by Kolmogorov\u27s theory of turbulent eddy lengths, and were substantially higher than the agitation rates required to keep microcarriers suspended. Identifying optimal pH, DO and agitation rates for microcarrier-based bioreactor expansion of adherent cells is paramount to developing a robust platform for use in a controlled manufacturing environment

AA MS 01 Gerald E. Talbot Collection Finding Aid

Description: Gerald E. Talbot was the first African American to be elected to the Maine State Legislature. He served in the Maine House of Representatives from 1972 to 1978, and worked with the Maine chapter of the NAACP and the State Board of Education. He also took part in the struggle for civil rights in other parts of the country, as well as in Maine. The Collection includes Talbot’s personal papers, records of his term in the Maine House of Representatives, of his work with the NAACP in Maine and with the State Board of Education. The Collection contains books, serials, posters, artifacts, and photographs documenting African Americans in the United States, with an emphasis on Maine. Date Range: ca. 1800s-1990s Size of Collection: 170 ft

Evaluating the Impact of a HIV Low-Risk Express Care Task-Shifting Program: A Case Study of the Targeted Learning Roadmap

In conducting studies on an exposure of interest, a systematic roadmap should be applied for translating causal questions into statistical analyses and interpreting the results. In this paper we describe an application of one such roadmap applied to estimating the joint effect of both time to availability of a nurse-based triage system (low risk express care (LREC)) and individual enrollment in the program among HIV patients in East Africa. Our study population is comprised of 16;513 subjects found eligible for this task-shifting program within 15 clinics in Kenya between 2006 and 2009, with each clinic starting the LREC program between 2007 and 2008. After discretizing followup into 90-day time intervals, we targeted the population mean counterfactual outcome (i.e. counterfactual probability of either dying or being lost to follow up) at up to 450 days after initial LREC eligibility under three fixed treatment interventions. These were (i) under no program availability during the entire follow-up, (ii) under immediate program availability at initial eligibility, but non-enrollment during the entire follow-up, and (iii) under immediate program availability and enrollment at initial eligibility. We further estimated the controlled direct effect of immediate program availability compared to no program availability, under a hypothetical intervention to prevent individualenrollment in the program. Targeted minimum loss-based estimation was used to estimate the mean outcome, while Super Learning was implemented to estimate the required nuisance parameters. Analyses were conducted with the ltmle R package; analysis code is available at an online repository as an R package. Results showed that at 450 days, the probability of in-care survival for subjects with immediate availability and enrollment was 0:93 (95% CI: 0.91, 0.95) and 0:87 (95% CI: 0.86, 0.87) for subjects with immediate availability never enrolling. For subjects without LREC availability, it was 0:91 (95% CI: 0.90, 0.92). Immediate program availability without individualenrollment, compared to no program availability, was estimated to slightly albeit significantly decrease survival by 4% (95% CI 0.03,0.06, p\u3c 0:01). Immediately availability and enrollment resulted in a 7% higher in-care survival compared to immediate availability with non-enrollment after 450 days (95% CI -0.08,-0.05, p\u3c 0:01). The results are consistent with a fairly small impact of both availability and enrollment in the LREC program on in-care survival

Modelling correlated variability in accreting black holes:the effect of high density and variable ionization on reverberation lags

We present a new release of the RELTRANS model to fit the complex cross-spectrum of accreting black holes as a function of energy. The model accounts for continuum lags and reverberation lags self-consistently in order to consider the widest possible range of X-ray variability timescales. We introduce a more self-consistent treatment of the reverberation lags, accounting for how the time variations of the illuminating flux change the ionisation level of the accretion disc. This process varies the shape of the reflection spectrum in time causing an additional source of lags besides the light crossing delay. We also consider electron densities in the accretion disc up to $10^{20}$ cm$^{-3}$, which are found in most of the stellar mass black holes and in some AGN. These high densities increase the amplitude of the reverberation lags below $1$ keV since the reflection flux enhances in the same energy range. In addition, we investigate the properties of hard lags produced by variations in the power-law index of the continuum spectrum, which can be interpreted as due to roughly $3\%$ variability in the corona's optical depth and temperature. As a test case, we simultaneously fit the lag energy spectra in a wide range of Fourier frequency for the black hole candidate MAXI J1820+070 observed with NICER. The best fit shows how the reverberation lags contribute even at the longer timescales where the hard lags are important. This proves the importance of modelling these two lags together and self-consistently in order to constrain the parameters of the system.Comment: Accepted for publication in MNRA

Proof of principle X-ray reflection mass measurement of the black hole in H1743-322

\ua9 2024 The Author(s). The black hole X-ray binary H1743-322 lies in a region of the Galaxy with high extinction, and therefore it has not been possible to make a dynamical mass measurement. In this paper, we make use of a recent model which uses the X-ray reflection spectrum to constrain the ratio of the black hole mass to the source distance. By folding in a reported distance measurement, we are able to estimate the mass of the black hole to be 12 \ub1 2 M☉ (1σ credible interval). We are then able to revise a previous disc continuum fitting estimate of black hole spin a∗ (previously relying on a population mass distribution) using our new mass constraint, finding a∗ = 0.47 \ub1 0.10. This work is a proof of principle demonstration of the method, showing it can be used to find the mass of black holes in X-ray binaries